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Luteolin is a natural flavonoid, which exists in many plants, including onions, broccoli, carrots, peppers, celery, olive oil, and mint. Luteolin is a dietary flavonoid with potent uric acid‐lowering and antioxidant bioactivities. To date, the mechanism by which luteolin alleviates hyperuricemia nephropathy (HN) still needs to be better defined. This study aims to evaluate the therapeutic efficacy of luteolin in a preclinical mouse model and in vitro. Luteolin was administered in the HN mice induced by the combination of potassium oxonate and hypoxanthine to evaluate the potential renoprotective effects in vivo. The NRK‐52E cells were stimulated with adenosine for in vitro evaluation. Hematoxylin and eosin staining, biochemical analysis, immunoblotting, immunofluorescence, and immunohistochemistry were performed for the histopathologic and mechanistic investigations. The results suggest that luteolin attenuated tubular dilation and epithelial atrophy in the renal tissue of HN mice. Further, luteolin improved biochemical indicators concerning renal functions and oxidative stress in vivo. Mechanistically, luteolin reduced the renal expressions of KIM‐1 and caspase‐3. Luteolin activated renal SIRT1/6 cascade and its downstream Nrf2‐mediated antioxidant pathway. Furthermore, luteolin elevated the renal expressions of ATP‐binding cassette subfamily G isoform 2 protein (ABCG2) and organic anion/cation transporters. In addition, livers of luteolin‐treated HN mice exhibited robust inhibition of xanthine oxidase. Together, our study shows that luteolin alleviates renal injury in the HN mice by activating urate excretion and Nrf2/HO‐1/NQO1 antioxidant pathways and inhibiting liver xanthine oxidase activity. Thus, luteolin may be a potential agent for the treatment of HN. [ABSTRACT FROM AUTHOR]

Abstract Hyperuricemic nephropathy (HN) is renal injury caused by hyperuricemia (HUA). While sleeve gastrectomy (SG) has shown promise in improving renal injury in patients with obesity-related HN, the mechanisms are not fully understood. This study induced an obesity-combined HN model in male ob/ob mice and measured serum uric acid (SUA), creatinine, and other biochemical indicators 6 weeks post-surgery. Renal histological changes were evaluated through staining techniques, and the study also assessed renal adenosine monophosphate-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation levels and urate transporter ABCG2 expression. In vitro experiments involved Nrf2 knockdown in AMPK-activated HK-2 cells and ChIP to confirm Nrf2 binding to the ABCG2 promoter. Results showed that SG reduced SUA levels, serum creatinine, and blood urea nitrogen, increased p-AMPK, p-Nrf2 protein, and ABCG2 expression, and alleviated renal fibrosis and inflammation. In vitro, Nrf2 knockdown down-regulated ABCG2 expression, and ChIP confirmed Nrf2’s role in ABCG2 transcription. The study suggests that SG may improve renal injury in HN mice by modulating the AMPK/Nrf2 pathway and upregulating ABCG2 transcription.

Objective: (MSU) crystals usually in the kidney tubules especially collecting ducts in the medulla. Previous animal models have not fully reproduced the impact of MSU on kidneys under non-hyperuricemic conditions. Methods: In the group treated with MSU, the upper pole of the rat kidney was injected intrarenally with 50 mg/kg of MSU, while the lower pole was injected with an equivalent volume of PBS solution. The body weight and kidney mass of the rats were observed and counted. H&E staining was used to observe the pathological damage of the kidney and to count the number of inflammatory cells. Masoon staining was used to observe the interstitial fibrosis in the kidneys of the rat model. Flow cytometric analysis was used for counting inflammatory cells in rats. ElISA was used to measure the concentration of serum and urine uric acid, creatinine and urea nitrogen in rats. Results: At the MSU injection site, a significantly higher infiltration of inflammatory cells and a substantial increase in the area of interstitial fibrosis compared to the control group and the site of PBS injection were observed. The serum creatinine level was significantly increased in the MSU group. However, there were no significant differences in the rats' general conditions or blood inflammatory cell counts when compared to the control group. Conclusion: The injection of urate crystals into the kidney compromised renal function, caused local pathological damage, and increased inflammatory cell infiltration and interstitial fibrosis. Intrarenal injection of MSU crystals may result in urate nephropathy. The method of intrarenal injection did not induce surgical infection or systemic inflammatory response. [ABSTRACT FROM AUTHOR]

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Uric acid (UA), the final product of human purine metabolism, can cause hyperuricemia (HUA) when excessively accumulated. HUA is closely linked to chronic kidney diseases (CKD) and is considered an independent risk factor. Hyperuricemic nephropathy, a form of CKD induced by HUA, has seen significant advances in understanding through research into the pathogenic roles of uric acid and the development of HUA animal models. Although progress has been made in understanding the pathophysiological mechanisms by which UA induces CKD, much remains to be learned about its pathological molecular mechanisms. New approaches in animal modeling or the selection of model animals may potentially lead to significant breakthroughs in research on hyperuricemia as well as related CKD. This paper reviews the research progress on the molecular mechanisms of hyperuricemic nephropathy, focusing on oxidative stress, inflammation, autophagy, fibrosis, and gut microbiota. Oxidative stress is induced by uric acid intracellularly through xanthine oxidase, NADPH oxidases, and mitochondria, leading to cellular damage. In terms of inflammation, uric acid crystals can activate the NLRP3 inflammasome, triggering an inflammatory cascade. The role of free uric acid as a pro-inflammatory agent, however, remains controversial. Depending on the study conducted, autophagy has been found to either alleviate or exacerbate inflammation induced by uric acid. Fibrosis, particularly through epithelial-mesenchymal transition (EMT), is a major mechanism by which uric acid causes glomerulosclerosis and tubulointerstitial fibrosis. Extensive research has explored various signaling pathways involved in uric acid-induced EMT. Beneficial gut microbiota protect the kidneys by synthesizing short-chain fatty acids, reducing urea’s enterohepatic circulation, and decreasing uric acid production. This paper aims to enhance understanding of the complex relationships between HUA and CKD, serving as a reference for further research and new drug development.

Uric acid (UA), the final product of human purine metabolism, can cause hyperuricemia (HUA) when excessively accumulated. HUA is closely linked to chronic kidney diseases (CKD) and is considered an independent risk factor. Hyperuricemic nephropathy, a form of CKD induced by HUA, has seen significant advances in understanding through research into the pathogenic roles of uric acid and the development of HUA animal models. Although progress has been made in understanding the pathophysiological mechanisms by which UA induces CKD, much remains to be learned about its pathological molecular mechanisms. New approaches in animal modeling or the selection of model animals may potentially lead to significant breakthroughs in research on hyperuricemia as well as related CKD. This paper reviews the research progress on the molecular mechanisms of hyperuricemic nephropathy, focusing on oxidative stress, inflammation, autophagy, fibrosis, and gut microbiota. Oxidative stress is induced by uric acid intracellularly through xanthine oxidase, NADPH oxidases, and mitochondria, leading to cellular damage. In terms of inflammation, uric acid crystals can activate the NLRP3 inflammasome, triggering an inflammatory cascade. The role of free uric acid as a pro-inflammatory agent, however, remains controversial. Depending on the study conducted, autophagy has been found to either alleviate or exacerbate inflammation induced by uric acid. Fibrosis, particularly through epithelialmesenchymal transition (EMT), is a major mechanism by which uric acid causes glomerulosclerosis and tubulointerstitial fibrosis. Extensive research has explored various signaling pathways involved in uric acidinduced EMT. Beneficial gut microbiota protect the kidneys by synthesizing short-chain fatty acids, reducing urea’s enterohepatic circulation, and decreasing uric acid production. This paper aims to enhance understanding of the complex relationships between HUA and CKD, serving as a reference for further research and new drug development. [ABSTRACT FROM AUTHOR]

Hyperuricemia is an independent risk factor for chronic kidney disease and contributes to renal fibrosis. This study aims to investigate the effect of Src family kinase (SFK) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN, feeding rats a mixture of adenine and potassium oxonate increased Src phosphorylation, severe glomerular sclerosis, and renal interstitial fibrosis, accompanied by renal dysfunction and increased urine microalbumin excretion. Administration of PP1, a highly selective SFK inhibitor, prevented renal dysfunction, reduced urine microalbumin, and inhibited activation of renal interstitial fibroblasts and expression of extracellular proteins. PP1 treatment also inhibited hyperuricemia-induced activation of the TGF-β1/Smad3, STAT3, ERK1/2, and NF-κB signaling pathways and expression of multiple profibrogenic cytokines/chemokines in the kidney. Furthermore, PP1 treatment significantly reduced serum uric acid levels and xanthine oxidase activity. Thus, blocking Src can attenuate development of HN via a mechanism associated with the suppression of TGF-β1 signaling, inflammation, and uric acid production. The results suggest that Src inhibition might be a promising therapeutic strategy for HN. [ABSTRACT FROM AUTHOR]

Hyperuricemia is an independent risk factor for chronic kidney disease (CKD) and promotes renal fibrosis, but the underlying mechanism remains largely unknown. Unresolved inflammation is strongly associated with renal fibrosis and is a well-known significant contributor to the progression of CKD, including hyperuricemia nephropathy. In the current study, we elucidated the impact of Caspase-11/Gasdermin D (GSDMD)-dependent neutrophil extracellular traps (NETs) on progressive hyperuricemic nephropathy. We found that the Caspase-11/GSDMD signaling were markedly activated in the kidneys of hyperuricemic nephropathy. Deletion of Gsdmd or Caspase-11 protects against the progression of hyperuricemic nephropathy by reducing kidney inflammation, proinflammatory and profibrogenic factors expression, NETs generation, α-smooth muscle actin expression, and fibrosis. Furthermore, specific deletion of Gsdmd or Caspase-11 in hematopoietic cells showed a protective effect on renal fibrosis in hyperuricemic nephropathy. Additionally, in vitro studies unveiled the capability of uric acid in inducing Caspase-11/GSDMD-dependent NETs formation, consequently enhancing α-smooth muscle actin production in macrophages. In summary, this study demonstrated the contributory role of Caspase-11/GSDMD in the progression of hyperuricemic nephropathy by promoting NETs formation, which may shed new light on the therapeutic approach to treating and reversing hyperuricemic nephropathy. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the preventive effect of Bi Xie Fen Qing Yin (BXFQY) decoction on hyperuricemic nephropathy (HN). Using an HN mouse model induced by oral gavage of potassium oxonate and adenine, we found that BXFQY significantly reduced plasma uric acid levels and improved renal function. Further study shows that BXFQY suppressed the activation of the NLRP3 inflammasome and decreased the mRNA expressions of pro-inflammatory and fibrosis-associated factors in renal tissues of HN mice. Also, BXFQY prevented the damage to intestinal tissues of HN mice, indicative of suppressed colonic inflammation and increased gut barrier integrity. By 16 S rDNA sequencing, BXFQY significantly improved gut microbiota dysbiosis of HN mice. On the one hand, BXFQY down-regulated the abundance of some harmful bacteria, like Desulfovibrionaceae, Enterobacter, Helicobacter, and Desulfovibrio. On the other hand, BXFQY up-regulated the contents of several beneficial microbes, such as Ruminococcaceae, Clostridium sensu stricto 1, and Streptococcus. Using gas or liquid chromatography-mass spectrometry (GC/LC-MS) analysis, BXFQY reversed the changes in intestinal bacterial metabolites of HN mice, including indole and BAs. The depletion of intestinal flora from HN or HN plus BXFQY mice confirmed the significance of gut microbiota in BXFQY-initiated treatment of HN. In conclusion, BXFQY can alleviate renal inflammation and fibrosis of HN mice by modulating gut microbiota and intestinal metabolites. This study provides new insight into the underlying mechanism of BXFQY against HN.

Hyperuricemia is an independent risk factor for chronic kidney disease. We have previously showed the uric-acid-lowering effect of Eurycoma longifolia Jack, yet the renal protective effect and mechanism of E. longifolia remain obscure. The mouse model of hyperuricemic nephropathy was induced by adenine combined with potassium oxonate in male C57BL/6 J mice. E. Longifolia alkaloid components could reduce the level of serum uric acid by regulating the expression of hepatic phosphoribosyl pyrophosphate synthase (PRPS), hypoxanthine-guanine phosphoribosyl transferase (HPRT), and renal urate transporter organic anion transporter 1 (OAT1) and ATP-binding box subfamily G member 2 (ABCG2) in HN mice. Additionally, E. Longifolia alkaloid components alleviated renal injury and function caused by hyperuricemia, which was characterized by improving renal histopathology, reducing urea nitrogen and creatinine levels. E. Longifolia alkaloid components treatment could reduce the secretion of pro-inflammatory factors by inhibiting the activation of NF-κB and NLRP3 inflammatory signaling pathways, including tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-1 β (IL-1β), and regulated activated normal T cell expression and secretion proteins (RANTES). Meanwhile, E. longifolia alkaloid components improved renal fibrosis, inhibited the transformation of calcium-dependent cell adhesion molecule E (E-cadherin) to α-smooth muscle actin (α-SMA) transformation, and decreased collagen 1 expression in HN mice. [ABSTRACT FROM AUTHOR]

Aim: Inflammation and apoptosis are main pathological processes that lead to the development of hyperuricemic nephropathy (HN). This study aims to explore whether baicalin (BA) and baicalein (BAI) can relieve the damage through PI3K/AKT/NF-κB signal pathway and provide more reliable and precise evidence for the treatment of HN. Methods: HN mice were induced by yeast extract with potassium oxonate (PO), and HK-2 cells were induced by monosodium urate (MSU). Molecular docking, western blot, q-PCR, and other methods were used to explore the changes of various indicators in HN mice and HK-2 cells. Results: Molecular docking results showed that BA and BAI had good binding ability with PI3K, AKT, p65 and IκBα. BA and BAI significantly ameliorated the levels of renal function, decreased the p-PI3K, p-AKT and p-p65 expression, down-regulated the BAX/BCL2 and CASP3, and blunted the mRNA levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-18 in both renal tissue of HN mice and HK-2 cells induced by MSU. BA and BAI also decreased the oxidative stress level of MSU-induced HK-2 cells. Conclusion: BA and BAI were confirmed to attenuate HN through alleviating renal inflammatory and apoptosis in cells and tissues by inhibiting PI3K/AKT/NF-κB pathway. BA and BAI were expected to be developed as new anti-HN drugs. [ABSTRACT FROM AUTHOR]

Hyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia, leading to hyperuricemia-associated renal abnormalities. The present review sheds light on the mechanistic aspects pertaining to HN, emphasizing the role of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in the occurrence and development of HN.This review recommends pharmacological inhibition of NLRP3 infammasome as a therapeutic strategy of HN treatment.

Mukaram Amatjan,1 Na Li,1 Pengke He,1 Boheng Zhang,1 Xianyan Mai,1 Qianle Jiang,1 Haochen Xie,2 Xiaoni Shao1 1Immunotherapy Laboratory, College of Pharmacology, Southwest Minzu University, Chengdu, 610225, People’s Republic of China; 2Qinghai Tibet Plateau Research Institute, Southwest Minzu University, Chengdu, 610225, People’s Republic of ChinaCorrespondence: Xiaoni Shao, Immunotherapy Laboratory, College of Pharmacology, Southwest Minzu University, #168 Dajian Street, Shuangliu District, Chengdu, 610225, People’s Republic of China, Tel +86-28-85738423, Email xnshao@swun.edu.cnBackground: Cichorium intybus L. formula (CILF) is a traditional Chinese medicine (TCM) widely used in the treatment of gout and hyperuricemic nephropathy (HN). The aim of this research was to investigate the potential protective effect of CILF against HN and elucidated the underlying mechanism.Methods: CILF water extract was administered to an HN rat model established by adenine combined with ethambutol. The levels of uric acid (UA), serum urea nitrogen (UREA), and creatinine (CREA) were detected. Changes in the pathology and histology of the kidney were observed by hematoxylin-eosin staining. The 16S rRNA of the gut microbiota was sequenced. The binding ability of the main ingredients of CILF to key targets was analyzed by network pharmacology and molecular docking. The expression levels of the related mRNAs and proteins in the kidney were evaluated by RT-qPCR and immunohistochemistry analysis.Results: CILF administration significantly alleviated increases in UA, UREA, and CREA, structural damage, and kidney dysfunction. Gut microbiota analysis was applied to explore the pharmacological mechanism of the effects of CILF on bacterial diversity and microbiota structure in HN. CILF decreased the abundance of Bacteroides. In addition, it increased the abundance of Lactobacillaceae, Erysipelotrichaceae, Lachnospiraceae, Ruminococcaceae, and Bifidobacterium. Based on network pharmacology and molecular docking analysis, CILF profoundly influenced the IL17, TNF and AGE-RAGE signaling pathway. Additionally, CILF inhibited the expression of STAT3, VEGFA and SIRT1 to improve the symptoms of nephropathy. Our research suggested that CILF protects against kidney dysfunction in rats with HN induced by adenine combined with ethambutol.Conclusion: Our findings on the anti-HN effects of CILF and its mechanism of action, from the viewpoint of systems biology, and elaborated that CILF can alter the diversity and community structure of the gut microbiota in HN, providing new approaches for the prevention and treatment of HN.Keywords: Cichorium intybus L. formula, hyperuricemic nephropathy, gut microbiota, network pharmacology, molecular docking

Hyperuricemia (HUA)-induced oxidative stress is a crucial contributor to hyperuricemic nephropathy (HN), but the molecular mechanisms underlying the disturbed redox homeostasis in kidneys remain elusive. Using RNA sequencing, together with biochemical analyses, we found that nuclear factor erythroid 2-related factor 2 (NRF2) expression and nuclear localization levels were increased in early HN progression and then gradually declined below the baseline level. We identified the impaired activity of the NRF2-activated antioxidant pathway as a driver of oxidative damage in HN progression. Through nrf2 deletion, we further confirmed aggravated kidney damage in nrf2 knockout HN mice compared with HN mice. In contrast, the pharmacological agonist of NRF2 improved kidney function and alleviated renal fibrosis in mice. Mechanistically, the activation of NRF2 signaling reduced oxidative stress by restoring mitochondrial homeostasis and reducing NADPH oxidase 4 (NOX4) expression in vivo or in vitro. Moreover, the activation of NRF2 promoted the expression levels of heme oxygenase 1 (HO-1) and quinone oxidoreductase 1 (NQO1) and enhanced the antioxidant capacity of cells. Furthermore, the activation of NRF2 ameliorated renal fibrosis in HN mice through the downregulation of the transforming growth factor-beta 1 (TGF-β1) signaling pathway and ultimately delayed the progression of HN. Collectively, these results suggested NRF2 as a key regulator in improving mitochondrial homeostasis and fibrosis in renal tubular cells by reducing oxidative stress, upregulating the antioxidant signaling pathway, and downregulating the TGF-β1 signaling pathway. The activation of NRF2 represents a promising strategy to restore redox homeostasis and combat HN. [ABSTRACT FROM AUTHOR]

Cyclocarya paliurus, as an important edible and medicinal plant, its effects and mechanisms on hyperuricemic nephropathy remain unclear. Herein, we investigated the hypouricemic and nephroprotective effects of the water extracts of C. paliurus leaves (CPE) in a hyperuricemic nephropathy rat model induced by adenine and ethambutol. The results showed that CPE could significantly decrease plasma uric acid (PUA) and urea nitrogen (PUN), as well as reduce renal fibrosis in the hyperuricemic nephropathy rat model. Plasma metabolomics indicated that CPE improved the disordered arachidonic acid metabolism. Meanwhile, CPE reduced renal inflammation via inhibition of COX--2. Moreover, CPE could improve disturbed purine metabolism by inhibiting the hepatic xanthine oxidase (XOD), reversing the renal urate transporter 1 (URAT1) and organic anion transporter 1 (OAT1). Collectively, this study demonstrated that CPE could exhibit hypouricemic effect by improving purine metabolism, and attenuate kidney injury by improving arachidonic acid metabolism and alleviating kidney inflammation.

Background: Hyperuricemic nephropathy is a highly prevalent kidney disease induced by excessive accumulation and deposition of monosodium urate in kidney, which contributes to the loss of kidney function. The Jiangniaosuan formulation (JNSF) is a Chinese herbal medicine treatment. The aim of this study is to evaluate its efficacy and safety among patients with hyperuricemic nephropathy at chronic kidney disease (CKD) stages 3–4 and with obstruction of phlegm turbidity and blood stasis syndrome. Methods: Our research is designed as a single-centre, double-blinded, randomized, placebo-controlled trial for 118 patients diagnosed with hyperuricemic nephropathy at CKD stages 3–4 and with obstruction of phlegm turbidity and blood stasis syndrome in mainland China. Patients are to be randomized into two groups: either the intervention group which receives JNSF 20.4 g/day combined with febuxostat 20–40 mg/day, or the control group which receives JNSF placebo 20.4 g/day combined with febuxostat 20–40 mg/day. The intervention will be carried on for 24 weeks. The change in estimated glomerular filtration rate (eGFR) is set as the primary outcome. Secondary outcomes include changes in serum uric acid, serum nitric oxide, urinary albumin/creatinine ratio, urinary N-acetyl-β-D glucosaminidase, urinary β2 microglobulin, urinary retinol binding protein and TCM syndromes in 24 weeks. Statistical analysis will be formulated by SPSS 24.0. Discussion: The trial will conduce to the comprehensive assessment in the efficacy and safety of JNSF among patients diagnosed with hyperuricemic nephropathy at CKD stages 3–4, and provide a clinical method available on systems of the combination of modern medicine and TCM.

Amyloidosis is a large group of diseases that occur through misfolding of extracellular proteins that accumulate in tissues and organs. Gout is the most common inflammatory arthritis worldwide and starts with the crystallization of uric acid within the joints and soft tissues. Although gouty arthritis is accompanied by inflammation, AA amyloidosis is rarely seen in patients with gout. Here we present a case of AA amyloidosis on the medullary sponge kidney in a 28‐year‐old man with gout. Our case had been diagnosed with gout 3 years previously, and his older brother was also diagnosed with early‐onset gout. As a result of the hyperuricemic nephropathy clinic and familial history, a whole gene sequence analysis was performed on the HPRT1 gene and UMOD gene, but no pathogenic changes were detected. Renal ultrasound revealed a bilateral medullary sponge kidney and amyloidosis was detected in the renal needle biopsy performed for the etiology of proteinuria. In our literature review, we found 16 cases in which gout was accompanied by AA amyloidosis. We present a 17th case and compare it with the other 16 cases. [ABSTRACT FROM AUTHOR]

Aim: Jian Pi Shen Shi Formula (JPSSF) is a beneficial treatment for hyperuricemia and related tissue damage in the clinical setting. This study was designed to investigate its therapeutic potential and underlying mechanisms in uricase‐deficient rats (Uox−/− rats). Methods: Uox−/− rats were used to assess the therapeutic potential of JPSSF on hyperuricemia. Protein extracts from renal tissues of a Uox−/− group and a JPSSF group were analyzed using tandem mass tag labeling quantitative proteomic workflow. Collagen deposition in Uox−/− rat kidneys was analyzed by Masson trichromatic staining. The gene expression associated with collagen‐binding‐related signaling pathways in the kidneys was further explored using quantitative polymerase chain reaction assay. The protein expressions of collagen 1a1 (col1a1), col6a1, and α‐smooth muscle actin were measured by Western blotting and immunohistochemistry. Results: JPSSF significantly decreased renal function indices and alleviated renal injuries. The action of JPSSF was manifested by down‐regulation of col6a1 and interleukin‐1 receptor‐associated kinase‐like 2, which blocked the binding sites on collagen and further prevented kidney injury. The anti‐renal fibrosis effect of JPSSF was confirmed by reducing the collagen deposition and hydroxyproline concentrations. JPSSF treatment also intensely down‐regulated the mRNA and protein expressions of col6a1, col1a1, and α‐smooth muscle actin, which inhibited the function of the collagen‐binding‐related signaling pathway. Conclusion: Our results indicated that JPSSF notably ameliorated hyperuricemia and related renal fibrosis in Uox−/− rats through lowering uric acid and down‐regulating the function of the collagen‐binding pathway. This suggested that JPSSF is a potential empirical formula for treating hyperuricemia and accompanying renal fibrosis. [ABSTRACT FROM AUTHOR]

Elevated levels of circulating fibroblast growth factor 21 (FGF21) have been reported in patients with hyperuricemia. However, the effect of FGF21 in hyperuricemic nephropathy (HN) remains unexplored. Here, we investigated the effect and mechanism of action of FGF21 on HN. HN model was induced with adenine and potassium oxysalt in wild‐type C57BL/6 mice and FGF21−/− mice. For in vitro studies, human renal tubular epithelial (HK‐2) cells were exposed to uric acid with/without FGF21 or β‐Klotho‐siRNA. Here, we reported aggravated renal dysfunction and structural damage in the FGF21−/− mice compared to the wild‐type mice. These were evident in the upsurge of inflammatory factors IL‐1β, TNF‐α, IL‐6, and IL‐18; fibrotic markers Collagen I and α‐SMA; and oxidation products ROS and MDA. However, exogenous administration of FGF21 to wild‐type HN mice significantly reversed these negative effects. In terms of mechanism, FGF21 significantly inhibited NF‐κB/NLRP3 and TGF‐β1/Smad3 pathways and promoted nuclear translocation of Nrf2 both in vivo and in vitro. Furthermore, the silencing of β‐Klotho was marked by the attenuation of the improved effect of FGF21 on cell damage. In conclusion, our studies revealed that exogenous FGF21 treatment significantly improved HN, which was achieved by the inhibition of inflammation, fibrosis, and oxidative stress. [ABSTRACT FROM AUTHOR]

Long-term hyperuricemia can induce kidney damage, clinically referred to as hyperuricemic nephropathy (HN), which is characterized by renal fibrosis, inflammation, and oxidative stress. However, currently used uric acid-lowering drugs are not capable of protecting the kidneys from damage. Therefore, uric acid-lowering drugs that can also protect the kidneys are urgently needed. In this study, we first discovered that salinomycin, an antibiotic, can regulate uric acid homeostasis and ameliorate kidney damage in mice with HN. Mechanistically, salinomycin inhibited serum and hepatic xanthine oxidase (XOD) activities and downregulated renal urate transporter 1 (URAT1) expression and transport activity, thus exerting uric acid-lowering effects in mice with HN. Furthermore, we found that salinomycin promoted p -NRF2 Ser40 expression, resulting in increased nuclear translocation of NRF2 and activation of NRF2. More importantly, salinomycin affected the gut microbiota and promoted the generation of short-chain fatty acids (SCFAs) in mice with HN. In conclusion, our results revealed that salinomycin maintains uric acid homeostasis and alleviates kidney injury in mice with HN by multiple mechanisms, suggesting that salinomycin might be a desirable candidate for HN treatment in the clinic. Salinomycin maintains the uric acid homeostasis in HN mice by inhibiting XOD and URAT1. Besides, it also improves renal fibrosis, inflammation and oxidative stress in HN mice by activating NRF2 and regulating gut microbiota as well as promoting SCFA production. The multiple effects of salinomycin contribute to its protective effect on the kidney damage in HN mice. [Display omitted] • Salinomycin decreases serum uric acid level via inhibiting XOD and URAT1 in HN mice. • Salinomycin alleviates renal fibrosis, inflammation and oxidative stress in HN mice. • Salinomycin improves kidney injury by regulating gut microbiota and promoting SCFAs production in HN mice. • Salinomycin ameliorates hyperuricemic nephropathy via regulating NRF2 pathway. [ABSTRACT FROM AUTHOR]

In this study, a combination of adenine and potassium oxonate was utilized to establish a hyperuricemic nephropathy (HN) mouse model, aiming to elucidate the effect through which Imperata Cylindrica polysaccharide (ICPC-a) ameliorates HN. In HN mice, an elevation in the abundance of Erysipelatoclostridium , Enterococcus , Prevotella , and Escherichia-Shigella was observed, whereas Lactobacillus and Bifidobacterium declined. Additionally, the systemic reductions in the levels of acetate, propionate, and butyrate, along with a significant increase in indole content, were noted. HN mice demonstrated intestinal barrier impairment, as evidenced by diminished mRNA expression of ZO-1, Occludin, and Claudin-1 and increased Mmp-9 levels. The pro-inflammatory factors IL-6, IL-17, TNF-α, IFN-γ, and COX-2 were overexpressed. Subsequent gavage intervention with ICPC-a markedly mitigated the inflammatory response and ameliorated colon tissue damage. ICPC-a effectively regulated the abundance of gut microbiota and their metabolites, including short-chain fatty acids (SCFAs), bile acids (BAs), and indole, promoting the correction of metabolic and gut microbiota imbalances in HN mice. These findings underscored the capacity of ICPC-a as a prebiotic to modulate gut microbiota and microbial metabolites, thereby exerting a multi-pathway and multi-targeted therapeutic effect on HN. • ICPC-a intervention attenuated intestinal barrier damage, maintaining intestinal tissue integrity. • ICPC-a corrected gut microbiota disturbances in HN mice • ICPC-a effectively regulated the imbalance of metabolic product levels in HN mice. [ABSTRACT FROM AUTHOR]

Hyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia. The pathogenesis of HN is directly related to urea metabolism in the gut microbiota. Febuxostat, a potent xanthine oxidase inhibitor, is the first-line drug used for the treatment of hyperuricemia. However, there have been few studies on the pharmacokinetics of febuxostat in HN animal models or in patients. In this study, a high-purine diet-induced HN rat model was established. The pharmacokinetics of febuxostat in HN rats was evaluated using LC-MS/MS. Astragaloside IV (AST) was used to correct the abnormal pharmacokinetics of febuxostat. Gut microbiota diversity analysis was used to evaluate the effect of AST on gut microbiota. The results showed that the delayed elimination of febuxostat caused drug accumulation after multiple administrations. Oral but not i. p. AST improved the pharmacokinetics of febuxostat in HN rats. The mechanistic study showed that AST could regulate urea metabolism in faeces and attenuate urea-ammonia liver-intestine circulation. Urease-related genera, including Eubacterium, Parabacteroides, Ruminococcus, and Clostridia, decreased after AST prevention. In addition, the decrease in pathogenic genera and increase in short-chain fatty acids (SCFA) producing genera also contribute to renal function recovery. In summary, AST improved the pharmacokinetics of febuxostat in HN rats by comprehensive regulation of the gut microbiota, including urea metabolism, anti-calcification, and short-chain fatty acid generation. These results imply that febuxostat might accumulate in HN patients, and AST could reverse the accumulation through gut microbiota regulation.

Coptisine, one of the main active components of Rhizoma Coptidis, possesses anti-inflammatory, antioxidant, anti-apoptosis and renoprotective effects. In this study, we investigated the protective effect of coptisine against hyperuricemia induced renal injury in vitro and in vivo, and determined the underlying mechanism. In the in vivo experiment, a mouse model of hyperuricemia induced acute renal injury was established using potassium oxonate (PO)/ hypoxanthine (HX), and in the in vitro experiment, HK-2 cells injury was induced by uric acid (UA). Results showed that coptisine treatment significantly attenuated the acute renal injury via reducing kidney weight and coefficient, UA, creatinine (CRE), blood urea nitrogen (BUN), and histological damages. Meanwhile, coptisine treatment significantly suppressed hyperuricemia induced oxidant stress, inflammatory injury and apoptosis through promoting superoxide dismutase (SOD) activity, restraining reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor (TNF)-α, interleukin (IL)− 1β, IL-18 levels, down-regulating protein expressions of cleaved-caspase 3, apoptosis-inducing factor (AIF), cyto-CytC, cleaved poly ADP-ribose polymerase (PARP) and Bcl-2-associated X protein (Bax), and up-regulating protein expressions of Bcl-2 and p-Bad. Additionally, mitochondrial structure damage and ATP depletion in renal tissue and HK-2 cells were observably alleviated. Of note, coptisine treatment remarkably ameliorated hyperuricemia induced phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (PKB/Akt) signaling pathway inhibition. When interference with Akt, the protective effect of coptisine against UA-induced injury in HK2 cells was reversed. All the results suggested that coptisine could protect against hyperuricemia induced renal inflammatory damage, oxidative stress and mitochondrial apoptosis via regulating PI3K/Akt signaling pathway.

Hyperuricemia (HUA), characterized by abnormal serum uric acid (UA) levels, is recognized as an important risk factor for hyperuricemic nephropathy (HN), which is strongly linked to gut microbiota. This study investigated the protective effects and regulatory mechanisms of insoluble fiber from barley leaves (BL) against HN, induced by adenine (Ad) and potassium oxonate (PO). The results showed that BL dramatically reduced the levels of serum UA and creatinine (CR) and alleviated renal injury and fibrosis. Moreover, BL modulated oxidative stress and downregulated the expression of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys of mice with HN. In addition, the 16S rRNA sequence data showed that BL also increased the relative abundance of short-chain fatty acids (SCFAs)-producing bacteria, including Bacteroides, Alloprevotella, and Eisenbergiella. Besides, BL treatment also increased SCFAs levels. Of interest, the application of SCFAs in hyperuricemic mice effectively reduced their serum UA. Furthermore, SCFAs dose-dependently inhibited URAT1 and GLUT9 in vitro and potently interacted with URAT1 and GLUT9 in the docking analysis. When taken together, our results indicate that BL and its metabolite SCFAs may be potential candidates for relieving HUA or HN. [ABSTRACT FROM AUTHOR]

Hyperuricemic nephropathy (HN) is characterized by increased serum uric acid levels that incite renal inflammation. While omega-3 polyunsaturated fatty acids (PUFAs) are known for their anti-inflammatory properties, their impact on HN remains unclear. This study explored the effects of omega-3 PUFAs, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), on HN. Using a mouse model induced by adenine and potassium oxonate, we treated HN mice with DHA, EPA, or both for four weeks. The results showed that omega-3 PUFAs significantly reduced serum uric acid levels and improved kidney function, with DHA, EPA, and their combination showing similar efficacy. Transcriptome sequencing and further analysis revealed that these fatty acids alleviate renal pyroptosis by reducing key markers such as NOD-like receptor pyrin containing 3 (NLRP3), cleaved gasdermin-D, caspase-1, and interleukin-1β. To further investigate the underlying mechanism, we focused on G-protein coupled receptor 120 (GPR120), a receptor activated by DHA. The use of a GPR120 antagonist (AH7614) partially blocked DHA's effects, while the agonist (TUG891) mimicked its anti-pyroptotic actions. Co-immunoprecipitation assays showed that DHA activates GPR120, leading to its internalization and interaction with β-arrestin2, ultimately inhibiting NLRP3 inflammasome formation and reducing inflammation. Overall, omega-3 PUFAs, particularly through GPR120 activation, appear to protect against renal inflammation in HN by modulating the NLRP3/caspase-1/GSDMD pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hyperuricemia is a common biochemical disorder, which resulted from both excessive uric acid (UA) production and/or absolute or relative impairment of urinary UA excretion. Growing evidence has indicated that hyperuricemia is an independent risk factor for the development and progression of chronic kidney disease (CKD), causing hyperuricemia-induced CKD (hyperuricemic nephropathy, HN). The therapeutic strategy of HN is managing hyperuricemia and protecting kidney function. Adverse effects of commercial drugs make persistent treatment of HN challenging. Traditional Chinese medicine (TCM) has exact efficacy in lowering serum UA without serious adverse effects. In addition, TCM is widely applied for the treatment of CKD. This review aimed to provide an overview of efficacy and mechanisms of traditional Chinese herbs and natural products in hyperuricemiainduced CKD. [ABSTRACT FROM AUTHOR]

Hyperuricemia always develops into hyperuricemic nephropathy (HN). The role of microRNA (miR) in HN is less studied. We aimed to discuss the role of miR-199a in HN. The expression of miR-199a and PPARγ in renal tissues of HN rats was detected. The targeting relation between miR-199a and PPARγ was verified. The contents of SCr, UA, BUN, and mALB, renal injury-relevant biomarkers were detected, and the pathological changes of renal tissue and renal interstitial fibrosis were observed by histological staining. After miR-199a and PPARγ knockdown, the contents of SCr, BUN, and mALB and renal interstitial fibrosis were estimated. Collectively, overexpression of miR-199a aggravated the renal injury in HN rats. By contrast, inhibition of miR-199a weakened renal injury, as evidenced by decreased contents of SCr, UA, BUN, and mALB, and mitigated renal interstitial fibrosis. miR-199a targeted PPARγ. Silencing of PPARγ upregulated the levels of downstream genes of β-catenin and the contents of SCr, UA, BUN, and mALB and deteriorated renal interstitial fibrosis. Moreover, the silencing of PPARγ blocked the alleviative effects of miR-199a inhibitor on the renal injury. Overall, miR-199a targets PPARγ and activates the β-catenin pathway, thus aggravating HN, which might provide a future target for the treatment of HN. [ABSTRACT FROM AUTHOR]

Urolithin A (UroA) is one of the primary intestinal metabolites of ellagitannins, showing translational potential as a nutritional intervention in humans. Mounting evidence suggests that fructose consumption contributes to the progression of chronic kidney disease (CKD) that manifests in hyperuricemic nephropathy, renal inflammation, and tubulointerstitial injury. Here, we investigated the efficacy of UroA in alleviating fructose-induced hyperuricemic nephropathy in mice. Uric acid-exposed human kidney-2 (HK-2) cells were utilized for in vitro mechanism validation. Histopathological staining, immunoblotting, and transmission electron microscope were performed for the mechanistic investigations. Our results revealed that UroA ameliorated fructose-induced hyperuricemic nephropathy in mice. The histopathologic assessment showed that UroA attenuated tubular hypertrophy and dilation, glomerular basement membrane thickening, and collagen deposition in the kidney of fructose-fed mice. Mechanistically, UroA treatment impaired STING-NLRP3 activation, resulting in reduced production of proinflammatory cytokines IL-1β, IL-6, and TNF-α. Notably, UroA exhibited a scavenging effect against reactive oxygen species (ROS) and restored fructose-impaired PINK1/Parkin-mediated mitophagy in nephropathic mice. Furthermore, the inhibitory effect of UroA in STING-NLRP3 activation was impaired after Parkin gene silencing in HK-2 cells. Together, this study suggests that UroA alleviates fructose-induced hyperuricemic nephropathy by promoting Parkin-dependent mitophagy, thereby suppressing STING-NLRP3 axis-mediated inflammatory response. Thus, dietary supplementation with UroA or ellagitannins-rich foods may serve as a promising intervention to prevent CKD progression. [ABSTRACT FROM AUTHOR]

• Hyperuricemia induces renal damage and reduces m6A methylation levels in the kidneys of mice. • Inhibition of uric acid reabsorption restores m6A methylation levels in mouse kidney tissue while alleviating renal injury. • Benzbromarone influences uric acid reabsorption in mice by reducing GLUT9 expression. • METTL14 downregulates GLUT9 expression by decreasing its mRNA stability in an m6A-dependent manner. Hyperuricemia is a known risk factor for chronic kidney disease (CKD) and subsequent renal fibrosis. N6-methyladenosine (m6A) is the most prevalent chemical modification in eukaryotic mRNAs and has been implicated in various diseases. However, its role in hyperuricemic nephropathy (HN) remains unclear. This study investigated the involvement of the methylase METTL14 in HN pathogenesis. Our in vitro and in vivo function experiments demonstrated that METTL14 plays a crucial role in HN. In mouse models of uric acid (UA)-induced renal injury, we detected impaired kidney function, increased renal interstitial fibrosis, and significantly decreased m6A methylation levels in renal tissues. Treatment with benzbromarone, a UA-lowering drug, alleviated renal injury, restored m6A methylation levels, and upregulated METTL14 expression. Cellular experiments showed that METTL14 overexpression attenuated high UA-induced fibrosis in renal tubular epithelial cells. This overexpression significantly decreases the expression of GLUT9, a key protein involved in UA transport, leading to reduced UA reabsorption. Additionally, MeRIP-qPCR and dual-luciferase reporter gene experiments further demonstrated that METTL14 overexpression enhanced Glut9 mRNA m6A methylation modification, accelerating its degradation and decreasing expression levels. Thus, METTL14-mediated RNA m6A modification plays a role in the renal tubular epithelial cell damage induced by high UA, by regulating Glut9 mRNA post-transcriptionally. These findings provide valuable insights for the diagnosis and development of therapeutic drugs for HN. [ABSTRACT FROM AUTHOR]

Diagnostic tools for the early detection of renal injury caused by hyperuricemia are still lacking. Here, we investigated whether contrast-enhanced ultrasound (CEUS) could be used as a diagnostic tool for hyperuricemic nephropathy (HN). In the HN rat model, CEUS detected a significant decline in renal cortical perfusion compared with that in control rats. Peak intensity (PI) values correlated significantly with serum KIM-1 levels and fibrosis scores in HN rats. An early decline in PI values was also observed in chronic kidney disease (CKD) stage 1 patients with HN compared with the controls (61.1±4.52 dB versus 65.80±7.10 dB) and correlated with renal function in the patients with HN. In contrast, an increase in time to reach PI values was detected in HN patients with stage 1 CKD (15.14±1.75 s versus 14.52±4.75 s) and was more pronounced in CKD stage 4 patients (67.32±3.29 s). CEUS was able to detect abnormal renal perfusion in early CKD with HN, which correlated with renal function decline, suggesting that CEUS could be used as a noninvasive tool for assessing renal function in patients with HN.

Urolithin A (UroA) is one of the primary intestinal metabolites of ellagitannins, showing translational potential as a nutritional intervention in humans. Mounting evidence suggests that fructose consumption contributes to the progression of chronic kidney disease (CKD) that manifests in hyperuricemic nephropathy, renal inflammation, and tubulointerstitial injury. Here, we investigated the efficacy of UroA in alleviating fructose-induced hyperuricemic nephropathy in mice. Uric acid-exposed human kidney-2 (HK-2) cells were utilized for in vitro mechanism validation. Histopathological staining, immunoblotting, and transmission electron microscope were performed for the mechanistic investigations. Our results revealed that UroA ameliorated fructose-induced hyperuricemic nephropathy in mice. The histopathologic assessment showed that UroA attenuated tubular hypertrophy and dilation, glomerular basement membrane thickening, and collagen deposition in the kidney of fructose-fed mice. Mechanistically, UroA treatment impaired STING-NLRP3 activation, resulting in reduced production of proinflammatory cytokines IL-1β, IL-6, and TNF-α. Notably, UroA exhibited a scavenging effect against reactive oxygen species (ROS) and restored fructose-impaired PINK1/Parkin-mediated mitophagy in nephropathic mice. Furthermore, the inhibitory effect of UroA in STING-NLRP3 activation was impaired after Parkin gene silencing in HK-2 cells. Together, this study suggests that UroA alleviates fructose-induced hyperuricemic nephropathy by promoting Parkin-dependent mitophagy, thereby suppressing STING-NLRP3 axis-mediated inflammatory response. Thus, dietary supplementation with UroA or ellagitannins-rich foods may serve as a promising intervention to prevent CKD progression.

Anti-partial epithelial-mesenchymal transition (pEMT) treatment of renal tubular epithelial cells (TECs) represents a promising therapeutic approach. Hyperuricemia nephropathy (HN) arises as a consequence of hyperuricemia (HUA)-induced tubulointerstitial fibrosis (TIF). Studies have suggested that the Ras homolog member A (RhoA)/Rho-associated kinase (ROCK) pathway is a crucial signaling transduction system in renal fibrosis. Fasudil, a RhoA/ROCK inhibitor, has exhibited the potential to prevent fibrosis progress. However, its impact on the pEMT of TECs in HN remains unclear. Here, an HN rat model and an uric acid (UA)-stimulated human kidney 2 (HK2) cell model were established and treated with Fasudil to explore its effects. Furthermore, the underlying mechanism of action involved in the attenuation of pEMT in TECs by Fasudil during HN was probed by using multiple molecular approaches. The HN rat model exhibited significant renal dysfunction and histopathological damage, whereas in vitro and in vivo experiments further confirmed the pEMT status accompanied by RhoA/ROCK pathway activation and oxidative stress in tubular cells exposed to UA. Notably, Fasudil ameliorated these pathological changes, and this was consistent with the trend of ROCK silencing in vitro. Mechanistically, we identified the Neh2 domain of nuclear factor erythroid 2-related factor 2 (Nrf2) as a target of Fasudil for the first time. Fasudil targets Nrf2 activation and antagonizes oxidative stress to attenuate the pEMT of TECs in HN. Our findings suggest that Fasudil attenuates oxidative stress-induced pEMT of TECs in HN by targeting Nrf2 activation. Thus, Fasudil is a potential therapeutic agent for the treatment of HN. [Display omitted] • Fasudil relieved renal dysfunction and TIF in HN rats. • Fasudil attenuated UA-induced pEMT in tubular cells. • UA-induced oxidative stress led to TIF in HN by promoting pEMT in tubular cells. • Fasudil targeted activation of Nrf2 for suppressing oxidative stress to defend against HN. [ABSTRACT FROM AUTHOR]

Hyperuricemia (HUA)-induced oxidative stress is a crucial contributor to hyperuricemic nephropathy (HN), but the molecular mechanisms underlying the disturbed redox homeostasis in kidneys remain elusive. Using RNA sequencing, together with biochemical analyses, we found that nuclear factor erythroid 2-related factor 2 (NRF2) expression and nuclear localization levels were increased in early HN progression and then gradually declined below the baseline level. We identified the impaired activity of the NRF2-activated antioxidant pathway as a driver of oxidative damage in HN progression. Through nrf2 deletion, we further confirmed aggravated kidney damage in nrf2 knockout HN mice compared with HN mice. In contrast, the pharmacological agonist of NRF2 improved kidney function and alleviated renal fibrosis in mice. Mechanistically, the activation of NRF2 signaling reduced oxidative stress by restoring mitochondrial homeostasis and reducing NADPH oxidase 4 (NOX4) expression in vivo or in vitro. Moreover, the activation of NRF2 promoted the expression levels of heme oxygenase 1 (HO-1) and quinone oxidoreductase 1 (NQO1) and enhanced the antioxidant capacity of cells. Furthermore, the activation of NRF2 ameliorated renal fibrosis in HN mice through the downregulation of the transforming growth factor-beta 1 (TGF-β1) signaling pathway and ultimately delayed the progression of HN. Collectively, these results suggested NRF2 as a key regulator in improving mitochondrial homeostasis and fibrosis in renal tubular cells by reducing oxidative stress, upregulating the antioxidant signaling pathway, and downregulating the TGF-β1 signaling pathway. The activation of NRF2 represents a promising strategy to restore redox homeostasis and combat HN.

Objective To explore the potential molecular mechanism of diosmetin in the treatment of hyperuricemic nephropathy（HN）based on network pharmacology and molecular docking. Methods Traditional Chinese medicine sys⁃ tem pharmacology database and analysis platform（TCMSP），SwissTargetPrediction database and ChEMBL database were used to screen the action target genes of diosmetin，HN-related target genes were searched with the GeneCards database， DisGeNET database，and the common target genes of diosmetin and HN were obtained by Venny 2. 1 online mapping tool. The protein-protein interaction（PPI）network of common target genes of diosmetin and HN was constructed based on STRING database，and the visualization analysis and topological analysis were carried out by using Cytoscape 3. 7. 0 soft⁃ ware to obtain the core target genes. GO functional annotation and Kyoto Encyclopedia of Genes and Genomes（KEGG） pathway enrichment analysis of common targets were analyzed by DAVID database. The protein encoded by the core target genes was taken as the receptor，and diosmetin as the ligand，and the molecular docking verification was carried out by AutoDock Vina 1. 1. 2. Results Totally 150 potential target genes of diosmetin and 443 HN-related target genes were ex⁃ cavated，and there were 22 common target genes of diosmetin and HN. The PPI network with common target genes includ⁃ ed 22 nodes and 85 edges. There were 8 core target genes，including TP53，XDH，ESR1，ABCG2，etc. Eighty-two GO functional items were obtained by enrichment analysis，including 51 biological processes（involving uric acid metabolism），13 cell compositions（involving cytoplasm），and 18 molecular functions（involving transmembrane transporter ac⁃ tivity）. Thirty-five KEGG signaling pathways were enriched，including TP53 signaling pathway，phosphatidylinositol 3 ki⁃ nase/protein kinase B（PI3K/Akt）signaling pathway，tumor necrosis factor（TNF）signaling pathway，nuclear factor kap⁃ pa-B（NF-κB）signaling pathway，etc. The results of molecular docking showed that the binding energy between diosmetin and the proteins encoded by eight core target genes such as TP53 was lower than -5 kcal/mol，and had strong binding activ⁃ ity. Conclusion Diosmetin may play a role in the treatment of HN by acting on core target genes such as TP53，XDH， ESR1 and ABCG2 pathway and then regulating TP53 signal pathway，PI3K/Akt signal pathway，TNF signal pathway，NFκB signal pathway and other pathways. [ABSTRACT FROM AUTHOR]

Hyperuricemia has become a common metabolic disease, and is a risk factor for multiple diseases, including chronic kidney disease. Our recent study indicated that following persistent uric acid stimulation, autophagy was activated in rats of hyperuricemic nephropathy (HN) and facilitated the development of renal fibrosis. Nevertheless, the potential mechanism by which autophagy promoted the progression of HN is still not fully elucidated. Thus, in the current study, we investigated the mechanisms of autophagy inhibition on the development of HN. Our data showed that autophagy was activated in human renal tubular cell lines (HK-2) exposure to uric acid. Inhibition of autophagy with 3-methyladenine (3-MA) and transfected with Beclin-1 siRNA prevented uric acid-induced upregulation of α-SMA, Collagen I and Collagen III in HK-2 cells. Moreover, uric acid upregulated autophagy via promoting the p53 pathway. In vivo , we showed that hyperuricemic injury induced the activation of NLRP3 inflammasome and pyroptosis, as evidenced by cleavage of caspase-1 and caspase-11, activation of gasdermin D (GSDMD) and the release of IL-1β and IL-18. Treatment with autophagy inhibitor 3-MA alleviated aforementioned phenomenon. Stimulation with uric acid in HK-2 cells also resulted in NLRP3 inflammasome activation and pyroptotic cell death, however treatment with 3-MA prevented all these responses. Mechanistically, we showed that the elevation of autophagy and degradation of autophagolysosomes resulted in the release of cathepsin B (CTSB), which is related to the activation of NLRP3 inflammasome. CTSB siRNA can inhibit the activation of NLRP3 inflammasome and pyroptosis. Collectively, our results indicate that autophagy inhibition protects against HN through inhibiting NLRP3 inflammasome-mediated pyroptosis. What's more, blockade the release of CTSB plays a crucial role in this process. Thus, inhibition of autophagy may be a promising therapeutic strategy for hyperuricemic nephropathy. [ABSTRACT FROM AUTHOR]

Hyperuricemia has become a common metabolic disease, and is a risk factor for multiple diseases, including chronic kidney disease. Our recent study indicated that following persistent uric acid stimulation, autophagy was activated in rats of hyperuricemic nephropathy (HN) and facilitated the development of renal fibrosis. Nevertheless, the potential mechanism by which autophagy promoted the progression of HN is still not fully elucidated. Thus, in the current study, we investigated the mechanisms of autophagy inhibition on the development of HN. Our data showed that autophagy was activated in human renal tubular cell lines (HK-2) exposure to uric acid. Inhibition of autophagy with 3-methyladenine (3-MA) and transfected with Beclin-1 siRNA prevented uric acid-induced upregulation of α-SMA, Collagen I and Collagen III in HK-2 cells. Moreover, uric acid upregulated autophagy via promoting the p53 pathway. In vivo, we showed that hyperuricemic injury induced the activation of NLRP3 inflammasome and pyroptosis, as evidenced by cleavage of caspase-1 and caspase-11, activation of gasdermin D (GSDMD) and the release of IL-1β and IL-18. Treatment with autophagy inhibitor 3-MA alleviated aforementioned phenomenon. Stimulation with uric acid in HK-2 cells also resulted in NLRP3 inflammasome activation and pyroptotic cell death, however treatment with 3-MA prevented all these responses. Mechanistically, we showed that the elevation of autophagy and degradation of autophagolysosomes resulted in the release of cathepsin B (CTSB), which is related to the activation of NLRP3 inflammasome. CTSB siRNA can inhibit the activation of NLRP3 inflammasome and pyroptosis. Collectively, our results indicate that autophagy inhibition protects against HN through inhibiting NLRP3 inflammasome-mediated pyroptosis. What’s more, blockade the release of CTSB plays a crucial role in this process. Thus, inhibition of autophagy may be a promising therapeutic strategy for hyperuricemic nephropathy.

Natural flavonoid pectolinarigenin (PEC) was reported to alleviate tubulointerstitial fibrosis of unilateral ureteral obstruction (UUO) mice in our previous study. To further investigate nephroprotective effects of PEC in hyperuricemic nephropathy (HN), adenine and potassium oxonate induced HN mice and uric acid-treated mouse kidney epithelial (TCMK-1) cells were employed in the study. As a result, PEC significantly lowered serum uric acid level and restored hyperuricemia-related kidney injury in HN mice. Meanwhile, PEC alleviated inflammation, fibrosis, and reduced adipokine FABP4 content in the kidneys of HN mice and uric acid-treated TCMK-1 cells. Mechanistically, PEC inhibited the TGF-β1 expression as well as the phosphorylation of transcription factor SMAD3 and STAT3 to regulate the corresponding inflammatory and fibrotic gene expression in kidney tissues. In conclusion, our results suggested that PEC could inhibit the activation of SMAD3 and STAT3 signaling to suppress inflammation and fibrosis, and thereby alleviate HN in mice. [ABSTRACT FROM AUTHOR]

Xin Wang,1,* Jin Deng,2,* Chongxiang Xiong,1 Haishan Chen,1 Qin Zhou,1 Yue Xia,1 Xiaofei Shao,1 Hequn Zou1 1Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Nephrology, The First Affiliated Hospital of University of South China, Hengyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hequn Zou Tel +86 020-62784391Email zhq1962@smu.edu.cnPurpose: Hyperuricemia is an independent risk factor for renal damage and can promote the progression of chronic kidney disease (CKD). In the present study, we employ a rat model to investigate the effects of rosiglitazone (RGTZ), a peroxisome proliferator-activated receptor-gamma agonist, on the development of hyperuricemic nephropathy (HN), and we elucidate the mechanisms involved.Methods: An HN rat model was established by oral administration of a mixture of adenine and potassium oxonate daily for 3 weeks. Twenty-four rats were divided into 4 groups: sham treatment, sham treatment plus RGTZ, HN, and HN treated with RGTZ.Results: Administration of RGTZ effectively preserved renal function, decreased urine microalbumin, and inhibited interstitial fibrosis and macrophage infiltration in a rat HN model. RGTZ treatment also inhibited TGF-β and NF-κB pathway activation, decreased expression of fibronectin, collagen I, α-SMA, vimentin, MCP-1, RANTES, TNF-α, and IL-1β, and increased E-cadherin expression in the kidneys of HN rats. Furthermore, RGTZ treatment preserved expression of OAT1 and OAT3 in the kidney of HN rats.Conclusion: RGTZ attenuates the progression of HN through inhibiting TGF-β signaling, suppressing epithelial-to-mesenchymal transition, reducing inflammation, and lowering serum uric acid levels by preserving expression of urate transporters.Keywords: hyperuricemic nephropathy, peroxisome proliferator-activated receptor-gamma, rosiglitazone, renal fibrosis, epithelial-to-mesenchymal transition, inflammation

Natural flavonoid pectolinarigenin (PEC) was reported to alleviate tubulointerstitial fibrosis of unilateral ureteral obstruction (UUO) mice in our previous study. To further investigate nephroprotective effects of PEC in hyperuricemic nephropathy (HN), adenine and potassium oxonate induced HN mice and uric acid-treated mouse kidney epithelial (TCMK-1) cells were employed in the study. As a result, PEC significantly lowered serum uric acid level and restored hyperuricemia-related kidney injury in HN mice. Meanwhile, PEC alleviated inflammation, fibrosis, and reduced adipokine FABP4 content in the kidneys of HN mice and uric acid-treated TCMK-1 cells. Mechanistically, PEC inhibited the TGF-β1 expression as well as the phosphorylation of transcription factor SMAD3 and STAT3 to regulate the corresponding inflammatory and fibrotic gene expression in kidney tissues. In conclusion, our results suggested that PEC could inhibit the activation of SMAD3 and STAT3 signaling to suppress inflammation and fibrosis, and thereby alleviate HN in mice.

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: (MSU) crystals usually in the kidney tubules especially collecting ducts in the medulla. Previous animal models have not fully reproduced the impact of MSU on kidneys under non-hyperuricemic conditions., Methods: In the group treated with MSU, the upper pole of the rat kidney was injected intrarenally with 50 mg/kg of MSU, while the lower pole was injected with an equivalent volume of PBS solution. The body weight and kidney mass of the rats were observed and counted. H&E staining was used to observe the pathological damage of the kidney and to count the number of inflammatory cells. Masoon staining was used to observe the interstitial fibrosis in the kidneys of the rat model. Flow cytometric analysis was used for counting inflammatory cells in rats. ElISA was used to measure the concentration of serum and urine uric acid, creatinine and urea nitrogen in rats., Results: At the MSU injection site, a significantly higher infiltration of inflammatory cells and a substantial increase in the area of interstitial fibrosis compared to the control group and the site of PBS injection were observed. The serum creatinine level was significantly increased in the MSU group. However, there were no significant differences in the rats' general conditions or blood inflammatory cell counts when compared to the control group., Conclusion: The injection of urate crystals into the kidney compromised renal function, caused local pathological damage, and increased inflammatory cell infiltration and interstitial fibrosis. Intrarenal injection of MSU crystals may result in urate nephropathy. The method of intrarenal injection did not induce surgical infection or systemic inflammatory response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Li, Chen, Ouyang, Lin, Wu, Fu, Quan, Wang, Wu, Yuan, Liu, Zhao, Liu, Zhu, Li and Mao.)

Hyperuricemia (HUA), characterized by abnormal serum uric acid (UA) levels, is recognized as an important risk factor for hyperuricemic nephropathy (HN), which is strongly linked to gut microbiota. This study investigated the protective effects and regulatory mechanisms of insoluble fiber from barley leaves (BL) against HN, induced by adenine (Ad) and potassium oxonate (PO). The results showed that BL dramatically reduced the levels of serum UA and creatinine (CR) and alleviated renal injury and fibrosis. Moreover, BL modulated oxidative stress and downregulated the expression of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys of mice with HN. In addition, the 16S rRNA sequence data showed that BL also increased the relative abundance of short-chain fatty acids (SCFAs)-producing bacteria, including Bacteroides, Alloprevotella, and Eisenbergiella. Besides, BL treatment also increased SCFAs levels. Of interest, the application of SCFAs in hyperuricemic mice effectively reduced their serum UA. Furthermore, SCFAs dose-dependently inhibited URAT1 and GLUT9 in vitro and potently interacted with URAT1 and GLUT9 in the docking analysis. When taken together, our results indicate that BL and its metabolite SCFAs may be potential candidates for relieving HUA or HN.

Hyperuricemia contributes to chronic kidney disease development. However, it has been historically viewed with limited research interest. In this study, we mimicked the development of hyperuricemic nephropathy by using a potassium oxonate‐induced hyperuricemia rat model. We found that administering vitamin C at 10 mg/kg/day effectively ameliorated hyperuricemic nephropathy. Compared to the control group, rats with hyperuricemia had significantly increased serum uric acid level, xanthine oxidase activity, and urine microalbumin level, by 5‐fold, 1.5‐fold, and 4‐fold, respectively. At the same time, vitamin C supplementation reverted these values by 20% for serum uric acid level and xanthine oxidase activity and 50% for microalbumin level. Vitamin C also alleviated renal pathology and decreased the expression of pro‐inflammatory and pro‐fibrotic markers. A further mechanistic study suggested that vitamin C might attenuate hyperuricemic nephropathy in renal tubular epithelial cells induced by monosodium urate (MSU) crystal, at least in part, by directly inhibiting IL‐6/JAK2/STAT3 signaling pathway. Meanwhile, in macrophages, vitamin C inhibited the expression of TGF‐β, and reduced ROS level induced by MSU by about 35%. In short, our results suggest that vitamin C supplementation delay the progression of hyperuricemic nephropathy. [ABSTRACT FROM AUTHOR]

Objective  To study the effect of norathyriol on uric acid excretion indicators in hyperuricemic nephropathy （HN） rats induced by adenine and potassium oxazinate.  Method  Sixty male SD rats were randomly divided into normal group, model group, norathyriol 1.0, 2.0, 4.0 mg/kg group, positive control benzbromarone 12.5 mg/kg group, each group of 10, according to 20 mL/kg volume were given respectively adenine （0.1 g/kg） and potassium oxonate （1.5 g/kg） suspension after 1 hour, and according to 10 ml/kg volume were given the test drug was administered once a day for 28 days. The gain weight of the rats was monitored weekly, and the urine was collected for 24 hours in themetabolic cage at 7, 14, 21 and 28 days after the administration. The urine volume, urine uric acid and urine creatinine were measured. At the end of the experiment, blood uric acid, serum creatinine and organ weight were measured. Uric acid excretion indicators were calculated: The fractional excretion of uric acid （FEUA）, the amount of 24 h uric acid excretion （24 h UUA）, creatinine clearance （CCr）, uric acid clearance （Cur）, glomerular load of uric acid （FLur）, excretion of uric acid per volume of glomerular filtration （EurGF） and ratio of urinary uric acid to creatinine.  Results  Norathyriol groups significantly reduced the level of serum uric acid in rats with hyperuricemic nephropathy. After 7 days of administration of 2.0 mg/kg norathyriol, 24 h UUA significantly increased （P < 0.05）. After 14 days and 28 days of administration of 2.0 mg/kg norathyriol, FEUA and Cur significantly increased （P < 0.05, P < 0.01）.  Conclusion  Norathyriol could affect FEUA and Cur, the sensitive indicators of uric acid excretion of rats with hyperuricemic nephropathy. [ABSTRACT FROM AUTHOR]

Hyperuricemic nephropathy (HN) is a renal injury caused by hyperuricemia and is the main cause of chronic kidney disease and end-stage renal disease. ShiWeiHeZiSan , which is composed mainly of components of Terminalia chebula Retz. And is recorded in the Four Medical Tantras, is a typical traditional Tibetan medicinal formula for renal diseases. Although T. chebula has been reported to improve renal dysfunction and reduce renal cell apoptosis, the specific mechanism of the nephroprotective effects of T. chebula on HN is still unclear. This study was conducted to evaluate the effects and specific mechanism of T. chebula extract on HN through network pharmacology and in vivo and in vitro experiments. Potassium oxalate (1.5 g/kg) and adenine (50 mg/kg) were combined for oral administration to establish the HN rat model, and the effects of T. chebula extract on rats in the HN model were evaluated by renal function indices and histopathological examinations. UPLC-Q-Exactive Orbitrap/MS analysis was also conducted to investigate the chemical components of T. chebula extract, and the potential therapeutic targets of T. chebula in HN were predicted by network pharmacology analysis. Moreover, the activation of potential pathways and the expression of related mRNAs and proteins were further observed in HN model rats and uric acid-treated HK-2 cells. T. chebula treatment significantly decreased the serum uric acid (SUA), blood urea nitrogen (BUN) and serum creatinine (SCr) levels in HN rats and ameliorated renal pathological injury and fibrosis. A total of 25 chemical components in T. chebula extract were identified by UPLC-Q-Exactive Orbitrap/MS analysis, and network pharmacology analysis indicated that the NF-κB pathway was the potential pathway associated with the therapeutic effects of T. chebula extract on HN. RT‒PCR analysis, immunofluorescence staining and ELISA demonstrated that the mRNA and protein levels of TLR4 and MyD88 were significantly decreased in the renal tissue of HN rats after treatment with T. chebula extract at different concentrations, while the phosphorylation of P65 and the secretion of TNF-α and IL-6 were significantly inhibited. The results of in vitro experiments showed that T. chebula extract significantly decreased the protein levels of TLR4, MyD88, p-IκBα and p-P65 in uric acid-treated HK-2 cells and inhibited the nuclear translocation of p65 in these cells. In addition, the expression of inflammatory factors (IL-1β, IL-6 and TNF-α) and fibrotic genes (α-SMA and fibronectin) was significantly downregulated by T. chebula extract treatment, while E-cadherin expression was significantly upregulated. T. chebula extract exerts nephroprotective effects on HN, such as anti-inflammatory effects and fibrosis improvement, by regulating the TLR4/MyD88/NF-κB axis, which supports the general use of T. chebula in the management of HN and other chronic kidney diseases. [Display omitted] • T. chebula alleviated renal injury and fibrosis in hyperuricemic nephropathy (HN). • 25 chemical components in T. chebula extract identified by UPLC-Q-Exactive MS/MS. • 74 H N therapeutic targets of T. chebula were screened by network pharmacology. • Nephroprotective effects of T. chebula on HN via regulating TLR4/MyD88/NF-κB axis. [ABSTRACT FROM AUTHOR]

Accumulating evidences indicated that hyperuricemia was an independent risk factor for kidney diseases and contributed to kidney fibrosis. Preventing and treating renal fibrosis was an optimal treatment for hyperuricemia-induced kidney diseases. In the study, pterostilbene (PTE) as a bioactive component of blueberries was confirmed to possess lowering serum uric acid and renal protective functions by the decrease of serum creatinine, BUN, urine albumin, and urine albumin-to-creatinine ratio (uACR) in a mouse model of hyperuricemic nephropathy (HN). Importantly, PTE treatment remarkably alleviated renal fibrosis of HN mice indicated by the downregulation of fibronectin, collagen I and α-SMA production. Furthermore, PTE could suppress the fibrosis-related protein expressions of TGF-β1/Smad3, Src and STAT3 in the kidneys of HN mice. In conclusion, PTE suppressed the activation of TGF-β1/Smad3, Src and STAT3 signaling pathway to alleviate renal fibrosis of HN mice, highlighting that PTE was a potential antifibrotic strategy for hyperuricemic nephropathy.

Hyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia. High-serum uric acid can trigger renal inflammation. The inflammasome family has several members and shows a significant effect on inflammatory responses. NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) senses the stimuli signal of excessive uric acid and then it recruits apoptosis-related specular protein (ASC) as well as aspartic acid-specific cysteine protease (caspase)-1 precursor to form NLRP3 inflammasome. NLRP3 inflammasome is activated in acute kidney injury (AKI), chronic kidney diseases (CKD), diabetic nephropathy (DN), and HN. This review focuses on important role for the involvement of NLRP3 inflammasome and associated signaling pathways in the pathogenesis of hyperuricemia-induced renal injury and the potential therapeutic implications. Additionally, several inhibitors targeting NLRP3 inflammasome are under development, most of them for experiment. Therefore, researches into NLRP3 inflammasome modulators may provide novel therapies for HN. [ABSTRACT FROM AUTHOR]