原发性痛风患者肾脏损害的原因分析

常染色体显性肾小管间质性肾病(autosomal dominant tubulointerstitial kidney disease，ADTKD)是一种罕见的常染色体显性小管间质性遗传性疾病，表现为高尿酸血症、痛风、尿浓缩功能受损和进行性肾衰竭。该病主要由尿调素(uromodulin，UMOD)基因变异引起。本文报告1个ADTKD家系，全外显子测序和Sanger测序鉴定先证者及其他患病亲属均携带UMOD基因错义变异c.761A>C(p.H254P)。美国医学遗传学和基因组学学会(American College of Medical Genetics and Genomics，ACMG)变异致病性分级评估该变异为疑似致病。该变异导致编码蛋白质的氨基酸序列发生改变，可能导致UMOD蛋白错误折叠和细胞内运输受损。UMOD变异与ADTKD相关，基因检测可为ADTKD早期临床诊断和治疗提供依据，在诊断罕见肾病中具有重要意义。

肾结石是一种病因复杂且易复发的常见疾病。人类基因组关联性研究发现多种基因突变导致的代谢缺陷与结石形成有关，其中单基因病例占比较高。基因突变引起酶功能、代谢通路、离子转运、受体敏感性等改变，导致草酸代谢、胱氨酸代谢、钙离子代谢、嘌呤代谢等缺陷，易产生遗传性肾结石。如原发性高草酸尿症、胱氨酸尿症、登特病、家族性低镁血症合并高钙尿和肾钙盐沉着症、巴特综合征、原发性远端肾小管酸中毒、婴儿高钙血症、遗传性低磷性佝偻病伴高钙尿症、腺嘌呤磷酸核糖基转移酶缺乏症、次黄嘌呤-鸟嘌呤磷酸核糖基转移酶缺乏症、遗传性黄嘌呤尿症等都与遗传性肾结石相关。本文就遗传性代谢缺陷所致肾结石的研究进展进行回顾，增加对草酸代谢、胱氨酸代谢、钙离子代谢、嘌呤代谢等缺陷致肾结石的认知，以便早期筛查、诊治及预防复发。

Abstract Introduction: Gout, characterized by hyperuricemia and urate crystal deposition, is associated with systemic inflammatory complications, including kidney injury. This study aimed to investigate the role of serum nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome and associated cytokines (IL-1β and IL-18) in gout-related kidney injury (GRI). Methods: A total of 279 gout patients (96 with renal injury and 183 without renal injury) and 100 healthy controls were included. Serum NLRP3, IL-1β, and IL-18 were measured and compared using an enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) analysis was carried out to evaluate the diagnostic values of individual or combinational biomarkers. Spearman's correlation analysis was employed to analyze correlations between NLRP3, IL-1β, and IL-18 and renal function indicators or serum uric acid. Results: Serum levels of NLRP3, IL-1β, and IL-18 were significantly higher in gout patients compared to healthy controls (p < 0.001, gout group with kidney injury [GKI]: n = 96, gout group without kidney injury [GNKI]: n = 183, controls: n = 100), with elevated levels observed in GKI patients compared to GNKI (p < 0.001). Correlations between these markers were confirmed among all gout patients (n = 279), including serum NLRP3 with IL-1β (r = 0.34, p < 0.001) and NLRP3 with IL-18 (r = 0.47, p < 0.001). ROC analysis revealed that the combined model of NLRP3, IL-1β, and IL-18 showed improved diagnostic accuracy for GRI, with an AUC of 0.85 (95% CI: 0.81–0.89, p < 0.001). In GKI patients (n = 96), serum NLRP3, IL-1β, and IL-18 were inversely correlated with eGFR (NLRP3: r = −0.43, p < 0.01). Additionally, serum IL-18 positively correlated with serum uric acid levels (r = 0.27, p = 0.009). Conclusion: These findings highlight the potential of serum NLRP3, IL-1β, and IL-18 as diagnostic markers and therapeutic targets in GRI, providing insights into early intervention and improved clinical outcomes in gout patients with renal complications.

Uric acid is a toxin retained with advancing kidney disease. Clinical manifestations of hyperuricemia include gout and systemic inflammation that are associated with increased risk for cardiovascular mortality. As many as one third of all patients with chronic kidney disease (CKD) have a history of gout, yet <25% of these patients are effectively treated to target serum urate levels of ≤6 mg/dL. A major reason for ineffective management of gout and hyperuricemia is the complexity in managing these patients, with some medications contraindicated, others requiring special dosing, potential drug interactions, and other factors. Consequently, many nephrologists do not primarily manage gout despite it being a common complication of CKD, leaving management to the primary physician or rheumatologist. We believe that kidney specialists should consider gout as a major complication of CKD and actively manage it in their patients. Here, we present insights from nephrologists and rheumatologists on a team approach to gout management that includes the nephrologist.

BACKGROUND Renal disease is prevalent in gouty patients and monosodium urate (MSU) crystal deposition in the kidney can be detected in some gouty nephropathy patients. MSU crystals can induce inflammatory events, we investigated the MSU-induced expression of intercellular adhesion molecule (ICAM)-1 on human renal mesangial cells (HRMCs) and the involved signal transduction mechanisms. METHODS The HRMCs cell line was purchased from ScienCell Research Laboratories. MSU crystals were made by dissolving uric acid in sodium hydroxide (NaOH) solution. The involvement of MAPKs, apoptosis-associated speck-like protein containing a CARD domain (ASC), and Toll-like receptor (TLR) was investigated using pharmacological inhibitors, transfection with short hairpin RNA (shRNA), or monoclonal antibodies. Protein expression was evaluated by Western blotting. The functional activity of ICAM-1 was evaluated with cell-cell adhesion assay and immunofluorescence analysis. RESULTS MSU stimulation increased expression of ICAM-1 and adhesion between HRMCs and human monocytic THP-1 cells. The interaction between HRMCs and THP-1 was suppressed by ICAM-1 neutralizing antibodies. MSU stimulation induced activation of mitogen-activated protein kinases, including c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK), but only p38 was responsible for MSU-induced expression of ICAM-1 and cell-cell adhesion. ASC also play a role in MSU-induced effects. Pretreatment with monoclonal antibodies against toll-like receptor (TLR)2 or TLR4 reduced MSU-induced ICAM-1 expression, cell-cell adhesion, p38 phosphorylation but the reduction of ASC activation is insignificant. CONCLUSION The MSU induced ICAM-1 expression on HRMCs and cell-cell adhesion involved TLR2/4-p38-ICAM1 pathway and TLR2/4 independent ASC-p38-ICAM1 axis. These findings might partly explain the mechanisms underlying gouty nephropathy.

Hyperuricemia nephropathy, also known as gouty nephropathy, refers to renal damage induced by hyperuricemia caused by excessive production of serum uric acid or low excretion of uric acid. the persistence of symptoms will lead to changes in renal tubular phenotype and accelerate the progress of renal fibrosis. The existence and progressive aggravation of symptoms will bring a heavy burden to patients, their families and society, affect their quality of life and reduce their well-being. With the increase of reports on hyperuricemia nephropathy, the importance of related signal pathways in the pathogenesis of hyperuricemia nephropathy is becoming more and more obvious, but most studies are limited to the upper and lower mediating relationship between 1 or 2 signal pathways. The research on the comprehensiveness of signal pathways and the breadth of crosstalk between signal pathways is limited. By synthesizing the research results of signal pathways related to hyperuricemia nephropathy in recent years, this paper will explore the specific mechanism of hyperuricemia nephropathy, and provide new ideas and methods for the treatment of hyperuricemia nephropathy based on a variety of signal pathway crosstalk and personal prospects.

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Abstract Hyperuricemia is a metabolic disorder characterized by elevated serum uric acid levels. Soluble urate can activate immune responses, and the excessive accumulation of urate in the kidneys results in hyperuricemic nephropathy (HN). However, the lack of an established HN model is a major obstacle to advancing research into the pathogenesis of HN and the development of novel drugs. In this study, we generated and evaluated an optimized mouse model of HN by the combined administration of potassium oxonate and hypoxanthine at various dosages. Our results demonstrated that intraperitoneal injection of 200 mg/kg potassium oxonate with gavage of 500 mg/kg hypoxanthine caused renal injury in mice, as evidenced by the elevation in serum uric acid, serum creatinine, and 24 h albuminuria levels, as well as pathological changes in renal histology. Intraperitoneal injection of 200 mg/kg potassium oxonate with gavage of 500 mg/kg hypoxanthine markedly increased the production of uric acid, inhibited uricase activity, and disrupted uric acid transporters. This led to supersaturated urate deposition in the kidneys, triggering renal inflammation and fibrosis, thereby promoting HN progression. In conclusion, we successfully established a stable and efficient mouse model that can mimic the pathogenesis of HN. This novel model may facilitate the discovery of therapeutic targets and the development of new drugs for the treatment of HN. Graphical Abstract

Urate nephropathy, a common complication of hyperuricemia, has garnered increasing attention worldwide. However, the exact pathogenesis of this condition remains unclear. Currently, inflammation is widely accepted as the key factor in urate nephropathy. Therefore, the aim of this study was to elucidate the interaction of lincRNA-p21/AIF-1/CMPK2/NLRP3 via exosomes in urate nephropathy. This study evaluated the effect of lincRNA-p21/AIF-1/CMPK2/NLRP3 using clinical data collected from patients with urate nephropathy and human renal tubular epithelial cells (HK2) cultured with different concentrations of urate. In clinical research section, the level of lincRNA-p21/AIF-1 in exosomes of urine in patients with hyperuricemia or urate nephropathy was found to be increased, particularly in patients with urate nephropathy. In vitro study section, the level of exosomes, inflammation, autophagy, and apoptosis was increased in HK2 cells induced by urate. Additionally, the expression of lincRNA-p21, AIF-1, CMPK2, and NLRP3 was upregulated in exosomes and HK2 cells. Furthermore, manipulating the activity of lincRNA-p21, AIF-1, CMPK2, and NLRP3 through overexpression or interference vectors regulated the level of inflammation, autophagy, and apoptosis in HK2 cells. In conclusion, the pathway of lincRNA-p21/AIF-1/CMPK2/NLRP3 contributed to inflammation, autophagy, and apoptosis of human renal tubular epithelial cell induced by urate via exosomes. Additionally, the specific exosomes in urine might serve as novel biomarkers for urate nephropathy.

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Hyperuricemic nephropathy (HN) is caused by urate crystals that get deposited in the kidney and contribute to renal fibrosis. Uric acid (UA) has been proven to directly cause renal mesangial cell oxidative stress and fibrosis in the pathogenesis of HN. Some antioxidants can be used as chemopreventive agents of HN. Hibiscus sabdariffa leaf extracts (HLE), rich in polyphenol, have been shown to possess hypoglycemic, antioxidant, hypolipidemic, antiatherosclerotic, and anticancer effects. The aim of the study is to examine the inhibitory effect of HLE and its main component ellagic acid (EA) on renal fibrosis. In vitro, mouse renal glomerular mesangial SV40MES13 cells pretreated with UA were demonstrated to trigger obvious morphological changes and viability loss, as well as affect matrix metalloproteinases (MMPs) activities. Noncytotoxic doses of HLE and EA abolished the UA-induced cell injury and MMP-2/9 secretion. In addition, HLE and EA exhibited antioxidant and anti-inflammatory effects on the UA-treated cells with a reduction in transforming growth factor-beta (TGF-β) production. Next, the UA-activated pro-fibrotic factors, extracellular matrix (ECM) deposition, and epithelial-mesenchymal-transition (EMT) were inhibited by HLE or EA. Mechanistic assays indicated that antifibrotic effects of HLE might be mediated via TGF-β/Smad signaling, as confirmed by the transfection of Smad7 siRNA. In vivo, HLE and EA supplementations significantly alleviated HN development, which may result from inhibiting adenine-induced TGF-β production accompanying oxidative stress and inflammation, as well as fibrogenesis. Our data imply that EA-enriched HLE regulates the TGF-β/Smad signaling, which in turn led to reduced renal mesangial cell injury and fibrosis in HN and provided a new mechanism for its nephroprotective activity.

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The sunflower (Helianthus annuus L.) calathide is gradually used as an alternative treatment for hyperuricemia; nevertheless, evidence regarding its main components and therapeutic capacity for urate nephropathy is lacking. Identification of sunflower calathide aqueous extract (SCE) was rapidly done by UPLC-ESI-Q-Orbitrap, and 32 water-soluble compounds with a comprehensive score >80 were discovered. Besides, yeast extract was administrated to induce high UA levels and hyperuricemic renal injury. We found that SCE treatment not only decreased UA levels to a comparable degree as allopurinol and benzbromarone, but also reduced the BUN levels and participated in kidney injury repair induced by uric acid. Moreover, it regulated the expression of URAT1 and ABCG2, especially inhibiting the GLUT9 in the normal kidney. Results were multifacetedly evaluated with a view to suggesting a possible mechanism of action as compared with those of allopurinol and benzbromarone by western blotting, H&E staining, and immunohistochemistry. However, the H&E staining showed histological changes in model, benzbromarone, and allopurinol groups rather than SCE treatments, and at the same time, the uric acid was identified as a cause of renal damage. The antiinflammatory effects and the regulations of COX-2/PGE2 signaling pathway were revealed on the LPS-induced RAW264.7 cells, indicating that the SCE not only increased cellular proliferation but also downregulated the COX-2, PGE2, NO, and IFN-γ cytokines in the RAW264.7 cells. To conclude, the SCE acts on urate transporters and contributes to prevent urate nephropathy via alleviating inflammatory process involving COX-2/PGE2 signaling pathway. It is available to develop SCE as food supplemental applications for hyperuricemia and nephritic inflammation.

The relationship between hyperuricemia, gout, and renal disease has been investigated for several years. From the beginning, kidney disease has been considered a complication of gout; however, the viewpoints changed, claiming that hypertension and elevated uric acid (UA) levels are caused by decreased urate excretion in patients with renal impairment. To date, several examples of evidence support the role of hyperuricemia in cardiovascular or renal diseases. Several mechanisms have been identified that explain the relationship between hyperuricemia and chronic kidney disease, including the crystal effect, renin–angiotensin–aldosterone system activation, nitric oxide synthesis inhibition, and intracellular oxidative stress stimulation, and urate-lowering therapy (ULT) has been proven to reduce renal disease progression in the past few years. In this comprehensive review, the source and physiology of UA are introduced, and the mechanisms that explain the reciprocal relationship between hyperuricemia and kidney disease are reviewed. Lastly, current evidence supporting the use of ULT to postpone renal disease progression in patients with hyperuricemia and gout are summarized.

Studies have shown that targeting xanthine oxidase (XO) can be a feasible treatment for fructose-induced hyperuricemia and hyperglycemia. This study aimed to evaluate the dual regulatory effects and molecular mechanisms of diacylated anthocyanins from purple sweet potato (diacylated AF-PSPs) on hyperglycemia and hyperuricemia induced by a high-fructose/high-fat diet. The body weight, organ index, serum biochemical indexes, and liver antioxidant indexes of mice were measured, and the kidneys were observed in pathological sections. The relative expression levels of messenger RNAs (mRNAs) of fructose metabolism pathway enzymes in kidney were detected by fluorescent real-time quantitative polymerase chain (qPCR) reaction technique, and the expression of renal transporter protein and inflammatory factor pathway protein was determined by immunohistochemistry (IHC) technique. Results showed that diacylated AF-PSPs alleviated hyperuricemia in mice, and that this effect might be related to the regulation of liver XO activity, lipid accumulation, and relevant renal transporters. Diacylated AF-PSPs reduced body weight and relieved lipid metabolism disorder, liver lipid accumulation, and liver oxidative stress, thereby enhancing insulin utilization and sensitivity, lowering blood sugar, and reducing hyperglycemia in mice. Also, diacylated AF-PSPs restored mRNA levels related to renal fructose metabolism, and reduced kidney injury and inflammation. This study provided experimental evidence for the mechanisms of dual regulation of blood glucose and uric acid (UA) by diacylated AF-PSPs and their utilization as functional foods in the management of metabolic syndrome. 多数研究已表明针对黄嘌呤氧化酶(XO)可以成为治疗果糖诱导的高尿酸血症和高血糖症的可行方法, 然而本研究旨在评估紫薯双酰基花色苷对高果糖/高脂肪饮食诱发的高血糖和高尿酸血症的双重调节作用及其分子机制。试验对小鼠体重、脏器指数、血清生化指标及肝脏抗氧化指标进行检测, 并对小鼠肾脏进行病理切片观察。利用实时荧光定量聚合酶链反应检测小鼠肾脏中果糖代谢通路酶的mRNA相对表达量, 同时, 利用免疫组织化学技术测定小鼠肾脏转运蛋白和炎症因子通路蛋白表达量。研究结果显示: 双酰基花色苷可以缓解小鼠的高尿酸血症, 这种作用可能与其调节肝脏XO活性、脂质积累和相关的肾脏转运蛋白有关; 紫薯双酰基花色苷能够减轻小鼠体重, 缓解小鼠脂质代谢紊乱, 降低肝脏脂质积累和肝脏氧化应激, 从而提高其胰岛素利用率和敏感性, 同时能够降低血糖, 减少高血糖的发生; 此外, 双酰基花色苷恢复了与肾脏果糖代谢有关的mRNA水平, 并减轻了肾脏损伤和炎症。这项研究为紫薯双酰基花色苷对血糖和尿酸的双重调节机制及其作为功能食品在代谢综合征治疗中的应用提供了实验依据。

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BACKGROUND Despite the increasing prevalence of hyperuricemia and gout, there remains a relative paucity of research focused on the use of straightforward clinical and laboratory markers to predict urate crystal formation. The identification of such predictive markers is crucial, as they would greatly enhance the ability of clinicians to make timely and accurate diagnoses, leading to more effective and targeted therapeutic interventions. OBJECTIVE The aim of this study was to evaluate the diagnostic value of various easily obtainable clinical and laboratory indicators and to establish a decision tree (DT) model to analyze their predictive significance for monosodium urate (MSU) deposition in the first metatarsophalangeal (MTP) joint. METHODS A retrospective study was conducted on 317 patients who presented to the outpatient clinic with a gout flare between January 2023 and June 2024 (181 cases with MSU deposition in the first MTP joint and 136 cases without such deposition). Clinical and laboratory indicators included gender, age, disease course, serum uric acid (SUA), glomerular filtration rate (GFR), serum creatinine (SCR), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Statistical analysis methods, including T-test, logistic regression and decision tree, were used to analyze the predictors of MSU deposition in the first MTP joint. The performance of the DT model was evaluated using receiver operating characteristic (ROC) curves and a 5-fold cross-validation method was used to ensure the robustness of the study results. RESULTS Disease course, GFR, SUA, age, and SCR emerged as significant predictors of MSU deposition in the first MTP joint in both LR and DT analyses. The DT model exhibited superior diagnostic performance compared to the LR model, with a sensitivity of 83.4% (151/181), specificity of 56.6% (77/136), and overall accuracy of 71.9% (228/317). The importance of predictive variables in the DT model showed disease course, GFR, SUA, age, and SCR as 53.36%, 21.51%, 15.1%, 5.5% and 4.53%, respectively. The area under the ROC curve predicted by the DT model was 0.752 (95% CI: 0.700~0.800). CONCLUSION The DT model demonstrates strong predictive capability. Disease duration, GFR, SUA, age, and SCR are pivotal factors for predicting MSU deposition at the first MTP joint, with disease course being the most critical factor.

Gout is caused by elevated serum urate leading to the deposition of monosodium urate (MSU) crystals that can trigger episodes of acute inflammation. Humans are sensitive to developing gout because they lack a functional urate-metabolizing enzyme called uricase/urate oxidase (encoded by the UOX gene). A hallmark of long-standing disease is tophaceous gout, characterized by the formation of tissue-damaging granuloma-like structures (‘tophi’) composed of densely packed MSU crystals and immune cells. Little is known about how tophi form, largely due to the lack of suitable animal models in which the host response to MSU crystals can be studied in vivo long-term. We have previously described a larval zebrafish model of acute gouty inflammation where the host response to microinjected MSU crystals can be live imaged within an intact animal. Although useful for modeling acute inflammation, crystals are rapidly cleared following a robust innate immune response, precluding analysis at later stages. Here we describe a zebrafish uox null mutant that possesses elevated urate levels at larval stages. Uricase-deficient ‘hyperuricemic’ larvae exhibit a suppressed acute inflammatory response to MSU crystals and prolonged in vivo crystal persistence. Imaging of crystals at later stages reveals that they form granuloma-like structures dominated by macrophages. We believe that uox−/− larvae will provide a useful tool to explore the transition from acute gouty inflammation to tophus formation, one of the remaining mysteries of gout pathogenesis.

Abstract Objective The present study was aimed to reveal the relationship between uric acid and fructose-induced obesity hypertension and its mechanisms. Methods A rat model with obesity hypertension was induced by a high-fructose diet. In the experiment I, the rats were fed with fructose for 8 wks along with allopurinol or benzbromarone at the beginning. In the experiment II, the rats were fed with fructose for 8 wks firstly. And then, these rats were treated with allopurinol or benzbromarone for additional 6 wks. Results Fructose-fed rats showed hyperuricemia, abdominal obesity hypertension and an activation in adipose renin-angiotensin system (RAS). Also, fructose-fed rats had higher levels of proinflammatory cytokines and more macrophages infiltrating in adipose tissue. In the experiment I, allopurinol and benzbromarone significantly reduced serum uric acid at 8 wk. Adipose RAS overactivation, adipose inflammatory responses and the development of obesity hypertension were all effectively prevented by hyperuricemia inhibition. In the experiment II, 6-wk treatment with allopurinol and benzbromarone significantly decreased serum uric acid, downregulated adipose RAS, abolished adipose inflammation and improved obesity hypertension. Conclusion In conclusion, urate-lowering therapy protects rats against fructose-induced obesity hypertension. The mechanisms appear to be via downregulated adipose RAS and reduced inflammation in adipose tissue.

Both hyperuricemia and adipose tissue renin-angiotensin system (RAS) are closely associated with multiple metabolic and cardiovascular diseases. We previously reported that uric acid could upregulate tissue RAS in adipocytes. In the present study, we aimed to reveal the involvement of toll-like receptors (TLRs) in uric acid-induced RAS activation in adipose tissue. A hyperuricemia rat model fed with a high-fructose diet and rat primary adipocytes were used in this study. Here, we inhibited TLR2 and TLR4 expression in adipose tissue and cultured adipocytes using small interfering RNA (siRNA). We found that high fructose-fed rats had hyperuricemia, higher body weight and greater adipose tissue content. We also found that hyperuricemia rats had raising blood pressure, higher expression levels of inflammatory cytokines and RAS components in adipose tissue, which could be prevented by TLR2/4-siRNA infection. In vitro study, uric acid caused a dose- and time-dependent increase in the mRNA expression of TLR2 and TLR4 in rat adipocytes. Uric acid could increase inflammatory cytokines and upregulate tissue RAS in rat adipocytes, which were both blocked with TLR2/4-siRNA infection. TNF-α and IL-6 could also result in an activation of tissue RAS expression in adipocytes. In conclusion, TLR2/4 mediated adipose inflammation plays a key role in RAS activation induced by uric acid in adipose tissue.

Apelin-13, a novel adipocytokine, is found to be a powerful antioxidant. Our previous work reported that uric acid could induce oxidative stress via an activation of renin-angiotensin system (RAS) in 3T3-L1 adipocytes. In the present study, we tried to observe the effect of apelin-13 on uric acid-induced oxidative stress. We also tried to reveal the potential mechanisms. In vivo, the rats were fed with 60% fructose diet for 8 weeks to produce hyperuricemia. Then, the hyperuricemia rats were intraperitoneally injected with apelin-13 for 2 weeks or 12 weeks. In vitro, 3T3-L1 adipocytes were treated with apelin-13 in the presence of 600 μmol/L uric acid for 48 h. When injected with apelin-13 for 12 weeks, the hyperuricemia rats had ameliorated oxidative stress, downregulated RAS components and upregulated angiotensin type 1 receptor related protein (APJ) expression in adipose tissue. Serum uric acid levels were also decreased after treatment. However, 2-week apelin-13 treatment had no obvious effect on the rats with hyperuricemia. Consistent with the findings in vivo, in vitro study, apelin-13 could ameliorate oxidative stress, decrease tissue RAS components, and increase APJ expression in 3T3-L1 adipocytes stimulated by uric acid. In conclusion, apelin-13 reduces uric acid-induced oxidative stress in adipose tissue, maybe through the inhibition of adipose RAS expression.

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BACKGROUND Experimental hyperuricemia is marked by an activated intrarenal renin-angiotensin system (RAS). The renal vascular response to exogenous angiotensin II (Ang II) provides an indirect measure of intrarenal RAS activity. We tested the hypothesis that the serum uric acid concentration predicts the renal vascular response to Ang II. METHODS A total of 249 subjects in high sodium balance had the renal plasma flow (RPF) response to Ang II measured. Para-aminohippuric acid (PAH) clearance was used to estimate RPF. Multivariable regression analysis determined if the serum uric acid concentration independently predicts the RPF response to Ang II. Variables considered included age, gender, race, body mass index (BMI), hypertension status, blood pressure, basal RPF, creatinine clearance, serum insulin, serum glucose, serum high-density lipoprotein (HDL), serum triglycerides, and plasma renin activity (PRA). RESULTS Uric acid concentration negatively correlated with the RPF response to Ang II (r=-0.37, P < 0.001). In univariate analysis, age, BMI, hypertension, triglycerides, and blood pressure were negatively associated, and basal RPF, HDL, and female gender were positively associated with the RPF response to Ang II. In multivariable analysis, serum uric acid concentration independently predicted the RPF response to Ang II (beta=-5.3, P < 0.001). CONCLUSION Serum uric acid independently predicted blunted renal vascular responsiveness to Ang II, consistent with results from experimental hyperuricemia showing an activated intrarenal RAS. This could be due to a direct effect of uric acid or reflect a more fundamental renal process. These data may have relevance to the association of uric acid with risk for hypertension and nephropathy.

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Background Prior research has highlighted the association between uric acid (UA) and the activation of the renin-angiotensin-aldosterone system (RAAS). However, the specific relationship between aldosterone, the RAAS’s end product, and UA-related diseases remains poorly understood. This study aims to clarify the impact of aldosterone on the development and progression of hyperuricemia and gout in hypertensive patients. Methods Our study involved 34534 hypertensive participants, assessing plasma aldosterone concentration (PAC)’s role in UA-related diseases, mainly hyperuricemia and gout. We applied multiple logistic regression to investigate the impact of PAC and used restricted cubic splines (RCS) for examining the dose-response relationship between PAC and these diseases. To gain deeper insights, we conducted threshold analyses, further clarifying the nature of this relationship. Finally, we undertook subgroup analyses to evaluate PAC’s effects across diverse conditions and among different subgroups. Results Multivariate logistic regression analysis revealed a significant correlation between the occurrence of hyperuricemia and gout and the elevation of PAC levels. Compared to the first quartile (Q1) group, groups Q2, Q3, and Q4 all exhibited a significantly increased risk of occurrence. Moreover, the conducted RCS analysis demonstrated a significant nonlinear dose-response relationship, especially when PAC was greater than 14 ng/dL, with a further increased risk of hyperuricemia and gout. Finally, comprehensive subgroup analyses consistently reinforced these findings. Conclusion This study demonstrates a close association between elevated PAC levels and the development of UA-related diseases, namely hyperuricemia and gout, in hypertensive patients. Further prospective studies are warranted to confirm and validate this relationship.

Chronic kidney disease (CKD) affects approximately 10-15% of adults globally and is a significant public health issue owing to its association with cardiovascular disease, end-stage kidney disease, and high healthcare costs. Hyperuricemia has emerged as an important modifiable risk factor influencing CKD progression. Elevated uric acid (UA) levels contribute to kidney injury through crystal-dependent mechanisms, including monosodium urate crystal deposition and NLRP3 inflammasome activation, and crystal-independent pathways, such as endothelial dysfunction, activation of the renin-angiotensin-aldosterone system, and oxidative stress. Observational studies have consistently linked hyperuricemia to an increased risk of CKD onset and accelerated disease progression. Nevertheless, randomized controlled trials and meta-analyses investigating UA-lowering therapy (ULT) for asymptomatic hyperuricemia have yielded conflicting results regarding its effectiveness in slowing CKD progression. Clinical guidelines also differ: Japanese guidelines recommend ULT for serum UA levels exceeding 8.0 mg/dL, whereas Western guidelines generally do not support routine treatment of asymptomatic hyperuricemia. Thus, there remains a clear need for large-scale, long-term studies to define patient subgroups most likely to benefit from ULT and guide individualized treatment approaches.

Asymptomatic hyperuricemia is defined by serum uric acid levels above 6.2 mg/dl in women and 7 mg/dl in men. In the presence of monosodium urate crystal formation and articular inflammation, hyperuricemia may become symptomatic (namely nephrolithiasis and gout). Uric acid results from purine catabolism and is at the centre of a complex metabolic interplay that involves oxidative stress, inflammation, renin-angiotensin-aldosterone system (RAAS) activation and insulin resistance. Uric acid levels present a continuous relation with conditions like hypertension and chronic kidney disease (CKD) and are reported to have an impact on risk of cardiovascular events. However, whether elevated uric acid is a causal agent and thus a possible therapeutic target is still uncertain and matter of further investigation. Treating symptomatic hyperuricemia involves lowering uric acid drugs and controlling inflammation. Urate-lowering agents are well tolerated but show minimal impact on cardiovascular events in patients with gout. Use of direct-acting urate-lowering agents in asymptomatic hyperuricemia associated with cardiovascular diseases does not warrant a clear benefit, whereas addressing cardiovascular issues with guideline-recommended therapies lowers uric acid and reduces the occurrence of cardiovascular events. Regular assessment of uric acid and clinical symptoms is advised before starting and renewing a urate-lowering treatment.

Accumulating evidence indicates that asymptomatic hyperuricemia is involved in the development of hypertension and chronic kidney disease. A two-hit model has been proposed to explain the role of urate in hypertension. The first hit entails activation of the renin-angiotensin system and inhibition of nitric oxide synthesis, which promote endothelial dysfunction, proliferation of vascular smooth-muscle cells and sodium reabsorption, leading to a moderate but consistent increase in systemic blood pressure. The second hit involves the immune system. Uric acid released in response to hypertension-induced damage can be recognized as a danger molecule by pattern recognition receptors, the sentinels of the innate immunity. Downstream signaling from these receptors leads to dendritic cell maturation and activation of resting T cells, but can also trigger the inflammasome and induce the secretion of proinflammatory cytokines. This proinflammatory milieu concurs in expanding the extracellular fluid volume and in increasing vascular resistances, which further promote systemic hypertension. Through similar mechanisms, hyperuricemia may also cause vascular and tubulointerstitial lesions that favor the development and progression of chronic kidney disease. To counteract these actions, xanthine oxidase inhibitors and uricosuric agents have been advocated as logical candidates to decrease the serum levels of uric acid. However, despite of a clear rationale for using hypouricemic drugs in patients with chronic kidney disease, there is currently a lack of robust evidence to sustain that lowering uric acid may slow the progression of renal disease.

Previous research has investigated whether hyperuricemia serves as an independent risk factor for cardiovascular and renal diseases. Hyperuricemia is defined as an abnormally high level of uric acid (UA; i.e., serum urate level > 6.8 mg/dL). Hyperuricemia has been considered a complication of chronic kidney disease (CKD). However, it seems to play a pathogenic role in the progression of renal diseases. There has been increasing focus on the link between hyperuricemia and CKD. The results of randomized controlled trials have implied independent associations between hyperuricemia and the progression of cardiovascular and renal morbidities. These associations may be mediated by renin-angiotensin system activation, nitric oxide synthase inhibition, and macrovascular/microvascular disease development. There remains controversy regarding the use of serum UA level as an indirect index of renal vascular disease. This literature review focuses on the role of asymptomatic hyperuricemia in the progression of CKD, as well as the association between hyperuricemia and cardiovascular disease. It also provides a general overview of the physiological metabolism of UA.

Hyperuricemia is an important risk factor for vascular inflammation, yet the potential mechanisms of uric acid (UA) in endothelial cells are not well understood. UA has been found to stimulate renin-angiotensin system (RAS) activation in human umbilical vein endothelial cells (HUVECs). (Pro)renin receptor ((P)RR) is widely expressed in endothelial cells and able to induce RAS activation. Whether UA-induced endothelial cell inflammation is via up-regulating (P)RR remained unknown. Primary HUVECs were cultured and treated with UA, under the condition of (P)RR or AT1 silencing. The degree of inflammation in HUVECs was determined by Real-time PCR and monocyte adhesion assay. The protein levels of (P)RR were determined by western blotting or immunofluorescence. Probenecid was used to block UA re-absorption in this study. Adhesion of monocytes to HUVECs was elucidated by microfluidic chip. We found (P)RR is up-regulated in HUVECs following UA stimulation. UA promoted vascular inflammation, which was characterized by up-regulating of cytokines and enhanced monocyte adhesion. Silencing of (P)RR alleviated UA-induced vascular inflammation. Probenecid treatment abolished UA-induced vascular inflammation in HUVECs via suppressing (P)RR up-regulation. This finding was further verified by using microfluidic chip. Our findings indicate that (P)RR plays a critical role in endothelial inflammation in response to UA stimulation.

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Renin angiotensin (Ang) system (RAS) activation in metabolic syndrome (MS) patients is associated with elevated uric acid (UA) levels, resulting in endothelial system dysfunction. Our previous study demonstrated that excessive UA could cause endothelial injury through the aldose reductase (AR) pathway. This study is the first to show that a high concentration of Ang II in human umbilical vein endothelial cells (HUVECs) increases reactive oxygen species (ROS) components, including O2·- and H2O2, and further aggravates endothelial system injury induced by high UA (HUA). In a MS/hyperuricemia model, nitric oxide (NO) production was decreased, followed by a decrease in total antioxidant capacity (TAC), and the concentration of the endothelial injury marker von Willebrand factor (vWF) in the serum was increased. Treatment with catalase and polyethylene glycol covalently linked to superoxide dismutase (PEG-SOD) to individually remove H2O2 and O2·- or treatment with the AR inhibitor epalrestat decreased ROS and H2O2, increased NO levels and TAC, and reduced vWF release. Taken together, these data indicate that HUA and Ang II act additively to cause endothelial dysfunction via oxidative stress, and specific elimination of O2·- and H2O2 improves endothelial function. We provide theoretical evidence to prevent or delay endothelial injury caused by metabolic diseases.

Oxidative stress induced by hyperuricemia is closely associated with the renin-angiotensin system, as well as the onset and progression of cardiovascular disease (CVD) and chronic kidney disease (CKD). It is therefore important to reduce oxidative stress to treat hyperuricemia. We previously found that benzbromarone, a uricosuric agent, has a direct free radical scavenging effect in vitro. The antioxidant effects of benzbromarone were evaluated in vivo via oral administration of benzbromarone for 4 weeks to model rats with angiotensin II- and salt-induced hypertension. Benzbromarone did not alter plasma uric acid levels or blood pressure but significantly reduced the levels of advanced oxidation protein products, which are oxidative stress markers. Furthermore, dihydroethidium staining of the kidney revealed a reduction in oxidative stress after benzbromarone administration. These results suggest that benzbromarone has a direct antioxidant effect in vivo and great potential to prevent CVD and CKD.

Uric acid exerts an important antioxidant effect against external oxidative stress under physiological conditions. However, uric acid itself can increase oxidative stress via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation in adipocytes and vascular cells. Uric acid transporter 1 is involved in the generation of this oxidative stress. Furthermore, uric acid locally activates the renin-angiotensin system, thus producing angiotensin II and subsequently increasing intracellular oxidative stress. Benzbromarone has been reported to suppress uric acid reabsorption via uric acid transporter 1 inhibition in renal tubular cells. In this study we evaluated the in vitro antioxidant effect of benzbromarone from several perspectives. First, the direct radical-trapping capacity of benzbromarone was measured by chemiluminescence assay and electron paramagnetic resonance spectroscopy. Second, the intracellular antioxidant activity of benzbromarone in hyperuricemia was evaluated using endothelial cells. In light of these results, benzbromarone is hypothesized directly to scavenge the superoxide anion radical. In addition, benzbromarone inhibited reactive oxygen species production that was induced by angiotensin II or uric acid in endothelial cells. These findings suggest that benzbromarone possesses the ability directly to scavenge radicals and may act as an antioxidant against uric acid and angiotensin II-induced oxidative stresses in endothelial cells at therapeutically achievable levels in blood.

Wuling capsule is a Chinese patent medicine mainly used for the treatment of chronic liver disease in clinical practice. Our previous work has revealed that Wuling capsule could inhibit liver fibrosis by regulating macrophage polarization, and firstly demonstrated its anti-gout effects on monosodium urate (MSU)- induced acute gouty arthritis (AGA) in rats. High uric acid (UA) levels are known to be the primary cause of gout. Therefore, this study investigated the UA lowering, kidney protection effects and underlying mechanisms of Wuling capsule in vivo and in vitro, and also determined its key bioactive constituents. The efficacy of Wuling capsule for HUA symptoms in rats was evaluated. Histopathological analysis of liver and kidney tissues were detected by HE staining. The biochemical indices were measured using specific kits. The main constituents of Wuling capsule and its medicated serum were analyzed by UPLC-QTOF-MS/MS. Protective effects of saikosaponin A, tanshinone IIA, schisandrol B, and ganoderic acid A on UA-injured HK-2 cells were assessed via Hoechst 33342/PI staining and flow cytometry. Molecular docking and dynamics simulation predicted the binding energy and stability of these constituents to UA related transporters. The mRNA and protein expression levels of UA related transporters were examined using RT-qPCR and Western blotting. In HUA rats, Wuling capsule significantly reduced the serum UA level and xanthine oxidase (XOD) content in both serum and liver. Furthermore, it improved liver function markers (ALT, AST) and renal injury indicators (Cr, BUN), ameliorated renal tubule dilation and inflammatory infiltration in the kidney, and regulated the mRNA and protein expression of UA related transporters (URAT1, GLUT9, ABCG2 and OAT1). In vitro, the main constituents of Wuling capsule (saikosaponin A, tanshinone IIA, schisandrol B and ganoderic acid A) improved cell viability and inhibited cell apoptosis in UA-injured HK-2 cells. Subsequently, its four serum constituents also significantly regulated the mRNA and protein expression of URAT1, GLUT9, and ABCG2 selectively. This work demonstrated the therapeutic effect of Wuling capsule on HUA by protecting liver and kidney function and regulating UA related transporters. These findings provide novel support for the further clinical application of Wuling capsule.

Hyperuricaemia is frequent in chronic kidney disease (CKD). Observational studies have shown an association with adverse outcomes and acquired hyperuricaemia (meaning serum urate levels as low as 1.0 mg/dL) in animal models induces kidney injury. This evidence does not justify the widespread use of urate-lowering drugs for asymptomatic hyperuricaemia in CKD. However, promising results from small, open-label studies led some physicians to prescribe urate-lowering drugs to slow CKD progression. Two recent, large, placebo-controlled trials (CKD-FIX and PERL) showed no benefit from urate lowering with allopurinol on the primary endpoint of CKD progression, confirming prior negative results. Despite these negative findings, it was still argued that the study population could be optimized by enrolling younger non-proteinuric CKD patients with better preserved glomerular filtration rate (GFR). However, in these low-risk patients, GFR may be stable under placebo conditions. Additionally, the increased mortality trends already identified in gout trials of urate-lowering therapy were also observed in CKD-FIX and PERL, sending a strong safety signal: 21/449 (4.7%) and 10/444 (2.2%) patients died in the combined allopurinol and placebo groups, respectively [chi-squared P-value 0.048; relative risk 2.07 (95% CI 0.98-4.34); P = 0.06]. Given the absent evidence of benefit in multiple clinical trials and the potentially serious safety issues, the clear message should be that urate-lowering therapy should not be prescribed for the indication of slowing CKD progression. Additionally, regulatory agencies should urgently reassess the safety of chronic prescription of urate-lowering drugs for any indication.

Chronic kidney disease (CKD) is a comorbid condition that affects, based on recent estimates, between 47% and 54% of patients with gouty arthritis. However, data from randomized controlled trials in patients with gouty arthritis and CKD are limited, and current gouty arthritis treatment guidelines do not address the challenges associated with managing this patient population. Nonsteroidal anti-inflammatory drugs and colchicine are recommended first-line treatments for acute gouty arthritis attacks. However, in patients with CKD, nonsteroidal anti-inflammatory drugs are not recommended because their use can exacerbate or cause acute kidney injury. Also, colchicine toxicity is increased in patients with CKD, and dosage reduction is required based on level of kidney function. Allopurinol, febuxostat, and pegloticase are all effective treatments for controlling elevated uric acid levels after the treatment of an acute attack. However, in patients with CKD, required allopurinol dosage reductions may limit efficacy; pegloticase requires further investigation in this population, and febuxostat has not been studied in patients with creatinine clearance<30 mL/min. This article reviews the risks and benefits associated with currently available pharmacologic agents for the management of acute and chronic gouty arthritis including urate-lowering therapy in patients with CKD. Challenges specific to primary care providers are addressed, including guidance to help them decide when to collaborate with, or refer patients to, rheumatology and nephrology specialists based on the severity of gout and CKD.

Two recent randomized clinical trials of escalating doses of allopurinol for the progression of chronic kidney disease (CKD) reported no benefits but potentially increased risk for death. Whether the risk could occur in patients with gout and concurrent CKD remains unknown. To examine the relation of allopurinol initiation, allopurinol dose escalation, and achieving target serum urate (SU) level after allopurinol initiation to all-cause mortality in patients with both gout and CKD. Cohort study. The Health Improvement Network U.K. primary care database (2000 to 2019). Patients aged 40 years or older who had gout and concurrent moderate-to-severe CKD. The association between allopurinol initiation and all-cause mortality over 5-year follow-up in propensity score (PS)-matched cohorts was examined. Analysis of hypothetical trials were emulated: achieving target SU level (<0.36 mmol/L) versus not achieving target SU level and dose escalation versus no dose escalation for mortality over 5-year follow-up in allopurinol initiators. Mortality was 4.9 and 5.8 per 100 person-years in 5277 allopurinol initiators and 5277 PS-matched noninitiators, respectively (hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.93]). In the target trial emulation analysis, the HR of mortality for the achieving target SU level group compared with the not achieving target SU level group was 0.87 (CI, 0.75 to 1.01); the HR of mortality for allopurinol in the dose escalation group versus the no dose escalation group was 0.88 (CI, 0.73 to 1.07). Residual confounding cannot be ruled out. In this population-based data, neither allopurinol initiation, nor achieving target SU level with allopurinol, nor allopurinol dose escalation was associated with increased mortality in patients with gout and concurrent CKD. Project Program of National Clinical Research Center for Geriatric Disorders.

Sustained, moderately severe hyperuricemia and severe uricosuria were produced in male Wistar rats by feeding dietary supplements of oxonic acid (0.4 gm. per day) and uric acid (0.6 gm per day). After 1 month, the kidneys showed the previously described histologic features of urate-blockade nephropathy characterized by intratubular deposits, tubular injury, and an exudative response consisting of neutrophilic granulocytes with early tophus formation. After 36 and 52 weeks of hyperuricemia, and with no gross evidence of renal failure, the kidneys showed a predominantly interstitial mononuclear cell infiltrate around regenerated tubules, an increase in interstitial fibrous tissue, infrequent renal tophi, and renal stones. The glomeruli and blood vessels appeared completely normal. There was no evidence of arthritis and no other target organ damage was detected. The chronic renal changes present in this animal model of induced hyperuricemia resemble those seen in human gouty nephropathy. The evolution of the experimental urate nephropathy observed during 1 year suggests that a primary acute inflammatory tubular injury is followed by a diffuse chronic interstitial nephritis and that the glomeruli and blood vessels are not primarily involved in the renal disease. This animal model may provide the opportunity to study factors influencing the renal sequelae of sustained hyperuricemia.

Hyperuricemia is an important pathological basis of gout and a distinct hazard factor for metabolic syndromes and cardiovascular and chronic renal disease, but lacks safe and effective treatments currently. Paeonia × suffruticosa Andrews leaf effectively reduced serum uric acid in gout patients; however, the material foundation and the mechanism remain unclear. To determine the primary active components and mechanism of P. suffruticosa leaf in hyperuricemic mice. The chemical constituents of P. suffruticosa leaf was identified using high-performance liquid chromatographic analysis. The anti-hyperuricemic activity of P. suffruticosa leaf extract (12.5, 25, 50, 100, and 200 mg/kg) and its components was evaluated in hyperuricemic mice induced by a high purine diet for 14 days. Then, the urate-lowering effects of apigenin 7-O-glucoside (0.09, 0.18, and 0.36 mg/kg) were assessed in another hyperuricemic mice model built by administrating potassium oxonate and adenine for 4 weeks. The inhibitory effect of apigenin 7-O-glucoside on uric acid production was elucidated by investigating xanthine oxidase activity in vitro and in serum and the liver and through molecular docking. Immunofluorescence and western blot analyses of the expression of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporters 1 (OAT1), and ATP-binding cassette G member 2 (ABCG2) proteins elucidated how apigenin 7-O-glucoside promoted uric acid excretion. Six compounds were identified in P. suffruticosa leaf: gallic acid, methyl gallate, oxypaeoniflorin, paeoniflorin, galloylpaeoniflorin, and apigenin 7-O-glucoside. P. suffruticosa leaf extract significantly attenuated increased serum uric acid, creatinine, and xanthine oxidase activity in hyperuricemic mice. Apigenin 7-O-glucoside from P. suffruticosa leaf reduced uric acid, creatinine, and malondialdehyde serum levels, increased superoxide dismutase activity, and partially restored the spleen coefficient in hyperuricemic mice. Apigenin 7-O-glucoside inhibited xanthine oxidase activity in vitro and decreased serum and liver xanthine oxidase activity and liver xanthine oxidase protein expression in hyperuricemic mice. Molecular docking revealed that apigenin 7-O-glucoside bound to xanthine oxidase. Apigenin 7-O-glucoside facilitated uric acid excretion by modulating the renal urate transporters URAT1, GLUT9, OAT1, and ABCG2. Apigenin 7-O-glucoside protected against renal damage and oxidative stress caused by hyperuricemia by reducing serum creatinine, blood urea nitrogen, malondialdehyde, and renal reactive oxygen species levels; increasing serum and renal superoxide dismutase activity; restoring the renal coefficient; and reducing renal pathological injury. Apigenin 7-O-glucoside is the main urate-lowering active component of P. suffruticosa leaf extract in the hyperuricemic mice. It suppressed liver xanthine oxidase activity to decrease uric acid synthesis and modulated renal urate transporters to stimulate uric acid excretion, alleviating kidney damage caused by hyperuricemia.

Uric acid, the end product of purine metabolism, is excreted predominantly by the proximal tubules. Abnormal serum levels of uric acid are due to alterations in production or excretion. Fractional excretion of uric acid is helpful in determining the underlying etiology of hypouricemia or hyperuricemia in children. Abnormalities in the molecular mechanisms that control renal uric acid tubular transport are implicated in various disorders associated with abnormal uric acid levels. Gout is rare in children; yet its presence necessitates evaluation for enzymatic defects in purine metabolism. Well-known effects of uric acid on the kidney include nephrolithiasis and acute kidney injury (AKI) in the setting of tumor lysis. However, recent data suggest that uric acid may be an important factor in the pathogenesis of AKI in general, as well as of chronic kidney disease (CKD) and hypertension. Hence, uric acid may not only be a marker but also a potential therapeutic target in kidney disease. Nonetheless, because of confounders, more studies are needed to clarify the association between uric acid and multifactorial disorders of the kidney.

Hyperuricemic nephropathy (HN) is a global metabolic disorder characterized by uric acid (UA) metabolism dysfunction, resulting in hyperuricemia (HUA) and tubulointerstitial fibrosis (TIF). Sodium-dependent glucose transporter 2 inhibitor, dapagliflozin, has shown potential in reducing serum UA levels in patients with chronic kidney disease (CKD), though its protective effects against HN remain uncertain. This study investigates the functional, pathological, and molecular changes in HN through histological, biochemical, and transcriptomic analyses in patients, HN mice, and UA-stimulated HK-2 cells. Findings indicate UA-induced tubular dysfunction and fibrotic activation, which dapagliflozin significantly mitigates. Transcriptomic analysis identifies estrogen-related receptor α (ERRα), a downregulated transcription factor in HN. ERRα knockin mice and ERRα-overexpressed HK-2 cells demonstrate UA resistance, while ERRα inhibition exacerbates UA effects. Dapagliflozin targets ERRα, activating the ERRα-organic anion transporter 1 (OAT1) axis to enhance UA excretion and reduce TIF. Furthermore, dapagliflozin ameliorates renal fibrosis in non-HN CKD models, underscoring the therapeutic significance of the ERRα-OAT1 axis in HN and CKD.

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The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (α-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-β (TGF-β) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-β signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy.

Gout is a clinical syndrome encompassing a group of metabolic diseases that are all characterized by abnormal uric acid metabolism. In its fullest form, gout is defined by: an increase in the serum urate concentration; characteristic, recurrent, acute arthritic attacks, with monosodium urate monohydrate crystals demonstrable in synovial fluid leukocytes; tophi, usually in and around joints of the extremities, composed of monosodium urate monohydrate deposits; renal disease, often accompanied by hypertension with glomerular, tubular, interstitial, and vascular involvement; and uric acid nephrolithiasis. Any combination of these manifestations may occur, although tophi and urate nephropathy rarely antedate gouty arthritis.

Uric acid is formed by catabolism of purine nucleotides. Approximately 25% is excreted through the intestines and the rest through the kidneys. A little less than 5% of the population in western industrialised countries have hyperuricaemia, primarily men and postmenopausal women. Hyperuricaemia is in most cases caused by reduced renal excretion, which may be idiopathic with otherwise normal renal function. But the condition is often associated with hypertension, nephropathy and treatment with diuretics and certain other drugs. Hyperuricaemia due to increased purine metabolism is seen in malignant haematological diseases, other conditions with increased cellular turnover and during initiation of chemotherapy in malignant diseases. Moreover hyperuricaemia is associated with some metabolic disturbances and risk factors of atherosclerotic cardiovascular disease including hypertension, overweight, insulin resistance and hyperlipidaemia. Hyperuricaemia is rarely caused by constitutional enzymatic abnormalities influencing purine metabolism. In most cases hyperuricaemia is asymptomatic. It may though be complicated by gout, urolithiasis and possibly gouty nephropathy. The risk of complications is correlated to the degree and duration of hyperuricemia. Consequently, measures to affect predisposing and associated conditions should be taken including weight reduction, physical exercise and diet guidance, treatment of hypertension and possibly changes in medication. Urate lowering drug treatment is normally not indicated in asymptomatic hyperuricaemic individuals.

Hyperuricemia (HUA) is closely associated with gut dysbiosis, yet the role of microbial metabolism in hyperuricemic nephropathy (HN) remains poorly understood. Quercetin has shown urate-lowering and nephroprotective effects, but its therapeutic mechanisms, particularly in modulating the gut microbiome and microbial metabolism, remain elusive. This study investigates the therapeutic effects of quercetin on HN and explores its role in regulating host-microbial co-metabolism. A spontaneous HUA rat model (Uox-/- rats) was used to evaluate the therapeutic effect of quercetin. Multi-omics analyses, including gut microbiome profiling, peripheral untargeted metabolome, and targeted quantification of gut bacteria-derived uremic toxins, were performed. An integrated network analysis was conducted to uncover potential host-microbe metabolic interactions. Quercetin treatment significantly reduced serum uric acid, creatinine, and blood urea nitrogen, ameliorated renal inflammation, fibrosis and oxidative stress, and improved gut dysbiosis and intestinal barrier dysfunction. Notably, high-dose quercetin downregulated Blautia, a key gut bacterium associated with uremic toxin production, and suppressed microbial phenylalanine metabolism, leading to decreased levels of gut bacteria-derived nephrotoxic metabolites (e.g., 3-phenyllactic acid, hippuric acid, and N-acetyl-l-phenylalanine). These uremic toxins were positively correlated with markers of kidney injury and proinflammatory cytokines. Mechanistically, quercetin modulated microbial enzymatic pathways involved in phenylalanine metabolism, thereby disrupting the formation of nephrotoxic metabolites and alleviating renal damage. This study provides multi-omics evidence that quercetin ameliorates HN by regulating gut dysfunctions and decreasing gut bacteria-derived uremic toxins through host-microbial co-metabolism. These findings highlight the therapeutic potential of microbiota-targeted interventions in HUA-associated kidney diseases.

Urate oxidase, or uricase (EC 1.7.3.3), is a purine metabolic enzyme that catalyzes the conversion of uric acid to allantoin in most mammals except humans and certain other primates. The loss of urate oxidase in the human during primate evolution predisposes man to hyperuricemia, a metabolic disturbance that can lead to gouty arthritis and renal stones. To create a mouse model for hyperuricemia and gout, and to address the question of whether urate oxidase is essential in lower mammalian species, we have disrupted the urate oxidase gene in the mouse by homologous recombination in embryonic stem cells. Unlike the human situation, urate oxidase deficiency in mice causes pronounced hyperuricemia and urate nephropathy. More than half of the mutant mice died before 4 weeks of age, indicating that urate oxidase is essential in mice. These mutant mice may also serve as animal models for hyperuricemia and its related nephropathy in humans.

Hyperuricemia (HUA) can lead to hyperuricemic nephropathy (HN) as a result of prolonged uric acid (UA) supersaturation, primarily characterized by excessive inflammation and oxidative stress. In clinical practice, the absence of specific drugs for HN treatment necessitates the use of urate-lowering drugs, despite their lack of reno-protective properties. Linarin, the principal pharmacological constituent of Chrysanthemum indicum L. (C. indicum L.), exhibits diverse bioactivities, including anti-inflammatory, antioxidant, and nephroprotective effects. However, there have been no reports on linarin's ability to mitigate HN, and the underlying mechanisms remain unexplored. This study aimed to investigate the mechanisms of linarin on ameliorating HN, with a particular emphasis on oxidative stress and inflammatory pathways. A HUA mouse model was developed using male ICR mice treated with hypoxanthine and potassium oxonate. Additionally, an adenosine-induced hyperuricemic cell model was established in NRK-52E cells. Following linarin treatment, serum UA levels and renal function parameters were assessed. The expression of proteins associated with UA production and excretion, oxidative stress, inflammation, and apoptosis was evaluated using western blot, immunohistochemical, and immunofluorescence analyses. Furthermore, Nrf2 knockout mice and Nrf2 inhibitor ML385 were utilized to investigate the mechanism of linarin on improving HN. Linarin significantly decreased the serum UA levels, inhibited XO activity and regulated UA transporter in the HUA mice. Moreover, linarin reversed the renal index, serum BUN and Cr levels, along with the expression levels of KIM-1, apoptosis-related molecules. Additionally, linarin obviously reduced the levels of TNF-α, IL-1β and IL-6, and alleviated renal inflammatory via suppressing the TLR4, p-NF-κB and p-IκBα levels. Furthermore, linarin was able to reverse the levels of SOD and MDA, and the expression of Nrf2, Keap1, NQO1, and HO-1 to mitigate oxidative stress both in vitro and in vivo. Inhibition of Nrf2 further confirmed that the renoprotective effect of linarin was linked to the activation of Nrf2. This study is the first to propose linarin as a potential natural compound for alleviating HN by modulating the Nrf2/Keap1 and TLR4/NF-κB signaling pathways, providing a promising strategy for HN.

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Urate oxidase (Uox)-deficient mice could be an optimal animal model to study hyperuricemia and associated disorders. We develop a liver-specific conditional knockout Uox-deficient (Uox

Long-term hyperuricemia (HUA) constitutes a major determinant of HUA-induced nephropathy (HN), yet current uricosuric drugs often exhibit limited efficacy and may pose a risk of kidney damage. Pregnane X receptor (PXR) plays a key role in xenobiotic and endobiotic metabolism homeostasis and has demonstrated anti-inflammatory, anti-fibrotic, and renoprotective properties. However, the role of PXR in regulating uric acid homeostasis and mitigating HN remains unclear. This study reveals PXR activation modulates uric acid homeostasis through dual suppression of xanthine oxidase (XOD) activity and enhanced ATP-binding cassette sub-family G member 2 (ABCG2) expression, thereby reducing uric acid accumulation and ameliorating renal injury. Mechanistically, PXR could interact with nuclear factor erythroid 2-related factor 2 (NRF2) to facilitate its nuclear translocation. Furthermore, we found that PXR activation inhibited K48-linked ubiquitination of NRF2 and promoted phosphorylation of NRF2 at S40, thereby activating NRF2 signaling and upregulating downstream target genes. This study elucidates PXR's dual role in regulating uric acid metabolism and attenuating HN, providing potential novel therapeutic targets for HN management.

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Hyperuricemia can induce acute and chronic kidney damage, but the pathological mechanism remains unclear. The potential role of AMP-activated protein kinase (AMPK) α2 in hyperuricemia-induced renal injury was investigated in this study. Acute and chronic hyperuricemic nephropathy was induced by administering intraperitoneal injections of uric acid and oxonic acid to AMPK α2 knockout and wild-type mice. Changes in renal function, histopathology, inflammatory cell infiltration, renal interstitial fibrosis, and urate deposition were analyzed. In both acute and chronic hyperuricemic nephropathy mouse models, knockout of AMPK α2 significantly reduced serum creatinine levels and renal pathological changes. The tubular expression of kidney injury molecule-1 was also reduced in hyperuricemic nephropathy mice deficient in AMPK α2. In addition, knockout of AMPK α2 significantly suppressed the infiltration of renal macrophages and progression of renal interstitial fibrosis in mice with chronic hyperuricemic nephropathy. Knockout of AMPK α2 reduced renal urate crystal deposition, probably through increasing the expression of the uric acid transporter, multidrug resistance protein 4. In summary, AMPK α2 is involved in acute and chronic hyperuricemia-induced kidney injury and may be associated with increased urate crystal deposition in the kidney.

No abstract

Protein S-nitrosylation (SNO), a redox-based posttranslational modification of cysteine thiols, plays a crucial role in various signaling pathways. Peroxiredoxin 2 (PRDX2) is one of the most potent ROS scavenging proteins, providing protection against oxidative stress damage, with its function regulated by SNO. However, the precise role of SNO-PRDX2 in hyperuricemic nephropathy remains poorly understood. In this study, we identified PRDX2 as a highly S-nitrosylated target in hyperuricemic nephropathy using a biotin switch assay. The elevation of SNO-PRDX2 was observed in kidneys of hyperuricemic mice as well as in uric acid (UA)-treated human renal tubular epithelial (HK-2) cells. S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, induced SNO modification of PRDX2, promoting mitochondrial dysfunction, oxidative stress, and cell apoptosis in HK-2 cells. Transfection with a plasmid containing a mutated cysteine 172 (Cys172) of PRDX2 yielded a decrease in SNO-PRDX2 levels in both hyperuricemic mice and UA-cultured HK-2 cells. Furthermore, administration of adeno-associated viruses carrying the Cys172-mutated PRDX2 significantly ameliorated renal interstitial fibrosis and reduced mitochondrial dysfunction, oxidative stress, and cell apoptosis in HUA-treated mice. In conclusion, our findings indicate that SNO modification of PRDX2 at Cys172 mediates HUA-induced kidney interstitial fibrosis, suggesting that SNO-PRDX2 may serve as a potential therapeutic target for HUA-induced renal injury.

Emodinol, 1β, 3β, 23-trihydroxyolean-12-en-28-acid, as the main active ingredient firstly extracted from the rhizomes of Elaeagus pungens by our Research Group, was identified with apparent uricosuric and nephroprotective effects in hyperuricemia mice in our previous study. This study aimed to investigate the renal protective effect of emodinol in urate nephropathy rats. Rats were orally administrated by combined adenine and ethambutol to induce urate nephropathy. Emodinol at various doses were administered intragastrically to urate nephropathy rats daily. Serum uric acid (Sur), serum creatinine (Scr) and blood urea nitrogen (BUN) levels, as well as Interleukin-1beta (IL-1β) and tumor necrosis factor- alpha (TNF-α) concentrations in serum and kidney were determined. Renal protein expressions of organic ion transporters, components of NLR pyrin domain containing 3 (NLRP3) inflammasome, as well as key factors involved in toll-like receptors (TLRs)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway were analyzed by western blot. Emodinol significantly decreased Sur, Scr and BUN levels in adenine and ethambutol - induced urate nephropathy rats. More importantly, emodinol reversed dys-expression of organic ion transporters, inhibited NLRP3 inflammsome activation and suppressed TLRs/MyD88/NF-κB signaling pathway in the kidneys of urate nephropathy rats. Consistently, dilated tubules and tubular UA crystal formation, as well as tubular interstitial inflammatory cells infiltration in kidneys of urate nephropathy rats were obviously attenuated by emodinol, accompanied by restored renal and serum inflammatory cytokines concentrations. Taken together, the date suggested that emodinol ameliorated urate nephropathy by regulating renal organic ion transporters and inhibiting immune inflammatory responses in rats.

Hyperuricemia and gout, the clinical manifestation of monosodium urate crystal deposition, are common in patients with chronic kidney disease (CKD). Although the presence of CKD poses additional challenges in gout management, effective urate lowering is possible for most patients with CKD. Initial doses of urate-lowering therapy are lower than in the non-CKD population, whereas incremental dose escalation is guided by regular monitoring of serum urate levels to reach the target level of <6mg/dL (or <5mg/dL for patients with tophi). Management of gout flares with presently available agents can be more challenging due to potential nephrotoxicity and/or contraindications in the setting of other common comorbid conditions. At present, asymptomatic hyperuricemia is not an indication for urate-lowering therapy, though emerging data may support a potential renoprotective effect.

Gout is the most common inflammatory arthritis and occurs when hyperuricaemia, sustained elevation of serum urate levels resulting in supersaturation of body tissues with urate, leads to the formation and deposition of monosodium urate crystals in and around the joints. Recent reports of the prevalence and incidence of gout vary widely according to the population studied and methods employed but range from a prevalence of <1% to 6.8% and an incidence of 0.58-2.89 per 1,000 person-years. Gout is more prevalent in men than in women, with increasing age, and in some ethnic groups. Despite rising prevalence and incidence, suboptimal management of gout continues in many countries. Typically, only a third to half of patients with gout receive urate-lowering therapy, which is a definitive, curative treatment, and fewer than a half of patients adhere to treatment. Many gout risk factors exist, including obesity, dietary factors and comorbid conditions. As well as a firmly established increased risk of cardiovascular disease and chronic kidney disease in those with gout, novel associations of gout with other comorbidities have been reported, including erectile dysfunction, atrial fibrillation, obstructive sleep apnoea, osteoporosis and venous thromboembolism. Discrete patterns of comorbidity clustering in individuals with gout have been described. Increasing prevalence and incidence of obesity and comorbidities are likely to contribute substantially to the rising burden of gout.

Hyperuricemia is highly prevalent, affecting approximately 38 million individuals in the United States. However, the significance of asymptomatic hyperuricemia - hyperuricemia in the absence of gout - continues to be debated. Asymptomatic hyperuricemia results in monosodium urate crystal deposition in tissues, which may promote chronic inflammation. Intracellularly, hyperuricemia inhibits the master regulator adenosine monophosphate (AMP)-associated protein kinase and may condition innate immune responses through durable epigenetic modifications. At the population level, asymptomatic hyperuricemia is associated with multiple comorbidities, including hypertension, chronic kidney disease, coronary artery disease, and diabetes; limitations of these studies include that most are retrospective and some do not rigorously distinguish between asymptomatic hyperuricemia and gout. Treatment studies suggest that urate lowering may reduce the risk of incidence or progression of some of these comorbidities; unfortunately, many of these treatment studies are small or flawed, and not all study results are consistent. Accumulating evidence suggests that asymptomatic hyperuricemia contributes to the comorbidities with which it associates and that proper asymptomatic hyperuricemia treatment may reduce future risk. Additional prospective trials are needed to definitely establish causality and support decision-making as to whether, and which patients with asymptomatic hyperuricemia would warrant urate-lowering treatment.

As a prominent feature of gout, monosodium urate (MSU) crystal deposition induces gout flares, but its impact on immune inflammation in gout remission remains unclear. Using single-cell RNA sequencing (scRNA-seq), we characterize the transcription profiling of peripheral blood mononuclear cells (PBMCs) among intercritical remission gout, advanced remission gout, and normal controls. We find systemic inflammation in gout remission with MSU crystal deposition at the intercritical and advanced stages, evidenced by activated inflammatory pathways, strengthened inflammatory cell-cell interactions, and elevated arachidonic acid metabolic activity. We also find increased HLA-DQA1

Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a 'danger signal' released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1beta activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1beta receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.

Hyperuricaemia (increased serum urate concentration) occurs mainly in higher primates, including in humans, because of inactivation of the gene encoding uricase during primate evolution. Individuals with hyperuricaemia might develop gout - a painful inflammatory arthritis caused by monosodium urate crystal deposition in articular structures. Hyperuricaemia is also associated with common chronic diseases, including hypertension, chronic kidney disease, type 2 diabetes and cardiovascular disease. Many mouse models have been developed to investigate the causal mechanisms for hyperuricaemia. These models are highly diverse and can be divided into two broad categories: mice with genetic modifications (genetically induced models) and mice exposed to certain environmental factors (environmentally induced models; for example, pharmaceutical or dietary induction). This Review provides an overview of the mouse models of hyperuricaemia and the relevance of these models to human hyperuricaemia, with an emphasis on those models generated through genetic modifications. The challenges in developing and comparing mouse models of hyperuricaemia and future research directions are also outlined.

Humans develop hyperuricemia via decreased urate elimination and excess urate production, consequently promoting monosodium urate crystal deposition and incident gout. Normally, approximately two-thirds of urate elimination is renal. However, chronic kidney disease (CKD) and other causes of decreased renal urate elimination drive hyperuricemia in most with gout. This places more demand on elimination of urate via the gut, where diet, purine metabolism, and microbiota intersect. Heritable impairment of urate transport into the gut is common and promotes hyperuricemia, renal urate overload, and early-onset and palpable tophaceous gout phenotypes. Lactobacilli, by sequestering and modifying ambient purines, are being studied for the potential to suppress diet-induced urate generation and associated gout flares. Landmark preclinical studies recently revealed much higher-capacity urate-lowering effects of diverse, obligate, and facultative anaerobic human and mouse gut microbiota (predominantly of the Bacillota phylum) termed purine-degrading bacteria (PDB). A conserved gene cluster in PDB drives urate conversion to lactate or anti-inflammatory short-chain fatty acids. When mice are rendered deficient in hepatic uricase to mimic human uricase absence, microbiota depletion rapidly elevates both cecal and serum urate, which is reversible by PDB administration. In healthy human volunteers with normal renal function, antibiotic-induced gut microbiota depletion decreases the urate-lowering gene cluster unique to PDB and elevates fecal urate. Also, prior exposure to antibiotics with anaerobic coverage has been linked to heightened incident gout risk. Notably, intestinal dysbiosis that includes Bacillota depletion has been observed in gout cohorts. Therefore, the capacity of diverse gut bacterial strains to biochemically compensate for human limits in urate disposition suggests novel probiotic treatment approaches for gout with inadequate pharmacologic control of both flares and hyperuricemia. This is particularly so for severe CKD, which limits the options and maximal doses for use of conventional oral urate-lowering drugs.

Gout is a clinical syndrome with a limited range of manifestations arising as a result of the deposition of crystals of monosodium urate, the final product of purine metabolism in humans. Hyperuricemia is a common chemical aberration that is most often mild and remains asymptomatic. Thus, hyperuricemia should be distinguished from gout, even though urate supersaturation is necessary for the expression of gout. Uric acid overproduction and diminished renal uric acid excretion are the major mechanisms resulting in hyperuricemia, and an understanding of the basis of hyperuricemia in individual gout patients is an important step in determining appropriate treatment and in identifying underlying disorders, offending drugs and toxins, and inherited enzyme defects, all of which can result in hyperuricemia and gout. A scheme is presented for the evaluation of patients with new-onset gout, along with a discussion of the relationships between gout/hyperuricemia and a variety of metabolic disorders that are unusually prevalent in gouty populations.

Gout is the most common inflammatory arthritis in men with a rising incidence worldwide. It is a metabolic disease caused by hyperuricemia. Common causes of hyperuricemia, in addition to hereditary reduced renal excretion of urate, include purine over-nutrition, aging, comorbidities and associated medications, some of which increase serum urate levels. The first gout flare represents the signal for deposited urate crystals. If hyperuricemia remains untreated, crystal deposition proceeds and can cause recurrent gout flares, joint destruction and tophi. There is evidence that silent inflammation is ongoing even during asymptomatic stages. Gout patients often exhibit other metabolic, renal and cardiovascular co-morbidities and have higher (cardiovascular) mortality. Therefore, guidelines call for consequent urate lowering strategies to bring serum urate levels to a target at least below 360 µmol/l. The following article summarizes the recent state of knowledge regarding the diagnosis and therapy of gout. Die Gicht, als häufigste Arthritis, wird durch Harnsäurekristalle ausgelöst. Ursächlich ist die Hyperurikämie, die meist aus einer renalen Harnsäureausscheidungsstörung, einem Zuviel an Purinen, aus Komorbiditäten und serumharnsäureerhöhenden Medikationen resultiert. Der erste Gichtanfall signalisiert abgelagerte Harnsäurekristalle – der Patient erhält eine Schmerztherapie. Danach gerät die Hyperurikämie oft in Vergessenheit, eine Harnsäuresenkung erfolgt nicht. Im interkritischen Intervall schreitet der Ablagerungsprozess fort, um nach Jahren mit Gichtanfällen und Gelenkdestruktionen sowie Nierenfunktionsverlust wieder aufzufallen. Daher fordern die Leitlinien bei sicherer Gicht eine Ursachensuche, diätetische Beratung und zielwertorientierte harnsäuresenkende Therapie. Wegen häufiger kardiometabolischer Begleiterkrankungen ist oft eine komplexe internistische Betreuung erforderlich. Im Folgenden werden die leitliniengerechte Diagnostik und Therapie der Gicht kompakt dargestellt.

The pathogenesis of gout involves a series of steps beginning with hyperuricaemia, followed by the deposition of monosodium urate crystal in articular structures and culminating in an innate immune response, mediated by the NLRP3 inflammasome, to the deposited crystals. Large genome-wide association studies (GWAS) of serum urate levels initially identified the genetic variants with the strongest effects, mapping mainly to genes that encode urate transporters in the kidney and gut. Other GWAS highlighted the importance of uncommon genetic variants. More recently, genetic and epigenetic genome-wide studies have revealed new pathways in the inflammatory process of gout, including genetic associations with epigenomic modifiers. Epigenome-wide association studies are also implicating epigenomic remodelling in gout, which perhaps regulates the responsiveness of the innate immune system to monosodium urate crystals. Notably, genes implicated in gout GWAS do not include those encoding components of the NLRP3 inflammasome itself, but instead include genes encoding molecules involved in its regulation. Knowledge of the molecular mechanisms underlying gout has advanced through the translation of genetic associations into specific molecular mechanisms. Notable examples include ABCG2, HNF4A, PDZK1, MAF and IL37. Current genetic studies are dominated by participants of European ancestry; however, studies focusing on other population groups are discovering informative population-specific variants associated with gout.

Gout is the most common inflammatory arthritis in men with a rising incidence worldwide. It is a metabolic disease caused by hyperuricemia. Common causes of hyperuricemia, in addition to hereditary reduced renal excretion of urate, include purine over-nutrition, aging, comorbidities and associated medications, some of which increase serum urate levels. The first gout flare represents the signal for deposited urate crystals. If hyperuricemia remains untreated, crystal deposition proceeds and can cause recurrent gout flares, joint destruction and tophi. There is evidence that silent inflammation is ongoing even during asymptomatic stages. Gout patients often exhibit other metabolic, renal and cardiovascular co-morbidities and have higher (cardiovascular) mortality. Therefore, guidelines call for consequent urate lowering strategies to bring serum urate levels to a target at least below 360 µmol/l. The following article summarizes the recent state of knowledge regarding the diagnosis and therapy of gout. Die Gicht, als häufigste Arthritis, wird durch Harnsäurekristalle ausgelöst. Ursächlich ist die Hyperurikämie, die meist aus einer renalen Harnsäureausscheidungsstörung, einem Zuviel an Purinen, aus Komorbiditäten und serumharnsäureerhöhenden Medikationen resultiert. Der erste Gichtanfall signalisiert abgelagerte Harnsäurekristalle – der Patient erhält eine Schmerztherapie. Danach gerät die Hyperurikämie oft in Vergessenheit, eine Harnsäuresenkung erfolgt nicht. Im interkritischen Intervall schreitet der Ablagerungsprozess fort, um nach Jahren mit Gichtanfällen und Gelenkdestruktionen sowie Nierenfunktionsverlust wieder aufzufallen. Daher fordern die Leitlinien bei sicherer Gicht eine Ursachensuche, diätetische Beratung und zielwertorientierte harnsäuresenkende Therapie. Wegen häufiger kardiometabolischer Begleiterkrankungen ist oft eine komplexe internistische Betreuung erforderlich. Im Folgenden werden die leitliniengerechte Diagnostik und Therapie der Gicht kompakt dargestellt.

Uric acid is a product of purine degradation, and uric acid may have multiple physiologic roles, including the beneficial effects as an antioxidant and neuroprotector, maintenance of blood pressure during low salt ingestion, and modulation of immunity. However, overproduction of metabolic uric acid, and/or imbalance of renal uric acid secretion and reabsorption, and/or underexcretion of extrarenal uric acid, e.g. gut, will contribute to hyperuricemia, which is a common metabolic disease. Long-lasting hyperuricemia can induce the formation and deposition of monosodium urate (MSU) crystals within the joints and periarticular structures. MSU crystals further induce an acute, intensely painful, and sterile inflammation conditions named as gout by NLRP3 inflammasome-mediated cleavage of pro-IL-1β to bioactive IL-1β. Moreover, hyperuricemia and gout are associated with multiple cardiovascular and renal disorders, e.g., hypertension, myocardial infarction, stroke, obesity, hyperlipidemia, type 2 diabetes mellitus and chronic kidney disease. Although great efforts have been made by scientists of modern medicine, however, modern therapeutic strategies with a single target are difficult to exert long-term positive effects, and even some of these agents have severe adverse effects. The Chinese have used the ancient classic prescriptions of traditional Chinese medicine (TCM) to treat metabolic diseases, including gout, by multiple targets, for more than 2200 years. In this review, we discuss the current understanding of urate homeostasis, the pathogenesis of hyperuricemia and gout, and both modern medicine and TCM strategies for this commonly metabolic disorder. We hope these will provide the good references for treating hyperuricemia and gout.

Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from damaged, dying, and dead cells. The kidney plays a dominant role in UA excretion, and the kidney excretes approximately 70% of daily produced UA; the remaining 30% of UA is excreted from the intestine. When UA production exceeds UA excretion, hyperuricemia occurs. Hyperuricemia is significantly associated with the development and severity of the metabolic syndrome. The increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome. Hyperuricemia was previously thought to be simply the cause of gout and gouty arthritis. Further, the hyperuricemia observed in patients with renal diseases was considered to be caused by UA underexcretion due to renal failure, and was not considered as an aggressive treatment target. The evidences obtained by basic science suggests a pathogenic role of hyperuricemia in the development of chronic kidney disease (CKD) and cardiovascular diseases (CVD), by inducing inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells, and activation of the renin-angiotensin system. Further, clinical evidences suggest that hyperuricemia is associated with the development of CVD and CKD. Further, accumulated data suggested that the UA-lowering treatments slower the progression of such diseases.

Gout is a disease caused by uric acid (UA) accumulation in the joints, causing inflammation. Two UA forms - monosodium urate (MSU) and soluble uric acid (sUA) have been shown to interact physically with inflammasomes, especially with the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3), albeit the role of the immune response to UA is poorly understood, given that asymptomatic hyperuricemia does also exist. Macrophage phagocytosis of UA activate NLRP3, lead to cytokines release, and ultimately, lead to chemoattract neutrophils and lymphocytes to the gout flare joint spot. Genetic variants of inflammasome genes and of genes encoding their molecular partners may influence hyperuricemia and gout susceptibility, while also influencing other comorbidities such as metabolic syndrome and cardiovascular diseases. In this review, we summarize the inflammatory responses in acute and chronic gout, specifically focusing on innate immune cell mechanisms and genetic and epigenetic characteristics of participating molecules. Unprecedently, a novel UA binding protein - the neuronal apoptosis inhibitor protein (NAIP) - is suggested as responsible for the asymptomatic hyperuricemia paradox.

Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting. In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping. Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney-specific or systemic RAS activity after 8 weeks or on mean systolic BP. These data do not support the hypothesis that higher levels of uric acid are a reversible risk factor for increased BP.

Experimental hyperuricemia is marked by an activated intrarenal renin-angiotensin system (RAS). The renal vascular response to exogenous angiotensin II (Ang II) provides an indirect measure of intrarenal RAS activity. We tested the hypothesis that the serum uric acid concentration predicts the renal vascular response to Ang II. A total of 249 subjects in high sodium balance had the renal plasma flow (RPF) response to Ang II measured. Para-aminohippuric acid (PAH) clearance was used to estimate RPF. Multivariable regression analysis determined if the serum uric acid concentration independently predicts the RPF response to Ang II. Variables considered included age, gender, race, body mass index (BMI), hypertension status, blood pressure, basal RPF, creatinine clearance, serum insulin, serum glucose, serum high-density lipoprotein (HDL), serum triglycerides, and plasma renin activity (PRA). Uric acid concentration negatively correlated with the RPF response to Ang II (r=-0.37, P < 0.001). In univariate analysis, age, BMI, hypertension, triglycerides, and blood pressure were negatively associated, and basal RPF, HDL, and female gender were positively associated with the RPF response to Ang II. In multivariable analysis, serum uric acid concentration independently predicted the RPF response to Ang II (beta=-5.3, P < 0.001). Serum uric acid independently predicted blunted renal vascular responsiveness to Ang II, consistent with results from experimental hyperuricemia showing an activated intrarenal RAS. This could be due to a direct effect of uric acid or reflect a more fundamental renal process. These data may have relevance to the association of uric acid with risk for hypertension and nephropathy.

A link between serum uric acid and the development of hypertension was first hypothesized in the 1870s. Although numerous epidemiologic studies in the 1980s and 1990s suggested an association, relatively little attention was paid to it until recently. Animal models have suggested a two-step pathogenesis by which uric acid initially activates the renin angiotensin system and suppresses nitric oxide, leading to uric acid-dependent increase in systemic vascular resistance, followed by a uric acid-mediated vasculopathy, involving renal afferent arterioles, resulting in a late sodium-sensitive hypertension. Initial clinical trials in young patients have supported these mechanisms in young patients but do not yet support pharmacologic reduction of serum uric acid as first-line therapy for hypertension.

We present the hypothesis that most cases of essential hypertension occur via two phases. The first phase is initiated by episodes of renal vasoconstriction induced by a hyperactive sympathetic nervous system, activation of the renin-angiotensin system, or hyperuricemia resulting from diet or genetics. During this phase the hypertension is salt resistant and renin dependent, and the kidney normal. Over time, preglomerular vascular disease develops (arteriolosclerosis), associated with tubulointerstitial inflammation; this shifts the hypertension to a salt-sensitive, volume-dependent, and renal-dependent pathway. This pathway unites many of the previous hypotheses on the etiology of hypertension, and offers insights into ways to prevent, ameliorate, or cure the underlying process.

Both hyperuricaemia and activation of the intrarenal renin-angiotensin system (RAS) play an important role in the development of hypertension and renal damage. However, it has not been clear whether hyperuricaemia is associated with renal damage due to hypertension or intrarenal RAS activation, as well as their circadian rhythms. We recruited 43 chronic kidney disease (CKD) patients who did not receive RAS blockers and antihyperuricaemic drugs, and investigated the relationship among serum uric acid (sUA) levels, the circadian rhythm of urinary angiotensinogen (U-AGT) excretion levels, and the levels of albuminuria (U-ACR) and proteinuria (U-P/Cr). sUA levels were significantly associated with estimated glomerular filtration rate (eGFR) (P = 0.002), systolic blood pressure (SBP) (daytime, P = 0.031), and U-ACR (daytime, P = 0.006 and nighttime, P = 0.008) and U-P/Cr (daytime, P = 0.017 and nighttime, P = 0.013). However, there were no significant differences between sUA levels and SBP in nighttime and U-AGT excretion levels in both time periods. Multiple regression analyses for sUA levels were performed using age, sex, eGFR and each parameter (SBP, U-AGT/Cr, U-ACR or U-P/Cr). sUA levels were not associated with SBP or U-AGT/Cr in both time periods. sUA levels tended to correlate with U-P/Cr levels in nighttime, and were significantly associated with U-P/Cr in daytime (P = 0.026) and U-ACR in daytime (P = 0.017) and nighttime (P = 0.046). Moreover, no significant differences were found between sUA levels and night-to-day ratios of some parameters. These data suggest that hyperuricaemia is associated with renal damage, independently of hypertension and intrarenal RAS activation, as well as their circadian rhythms.