potassium-oxonate and Kidney-Diseases

Phellodendri Chinensis Cortex (PC) is a traditional medicinal material used to treat gout and hyperuricemia (HUA) in China. Berberine (BBR), the main component of PC, possesses anti-hyperuricemic and anti-gout effects. However, BBR exhibits low bioavailability due to its extensive metabolism and limited absorption. Thus, the metabolites of BBR are believed to be the potential active forms responsible for its in vivo biological activities. Berberrubine (BRB), one of the major metabolites of BBR, exhibits appreciable biological activities even superior to BBR. In this work, the anti-hyperuricemic efficacy of BRB was investigated in HUA model mice induced by co-administration with intraperitoneal potassium oxonate (PO) and oral hypoxanthine (HX) for 7 days. Results showed that administration with BRB (6.25, 12.5, and 25.0 mg/kg) significantly decreased the serum levels of uric acid (UA) by 49.70%, 75.35%, and 75.96% respectively, when compared to the HUA group. In addition, BRB sharply decreased the levels of blood urea nitrogen (BUN) (by 19.62%, 28.98%, and 38.72%, respectively) and serum creatinine (CRE) (by 16.19%, 25.07%, and 52.08%, respectively) and reversed the PO/HX-induced renal histopathological damage dose-dependently. Additionally, BRB lowered the hepatic XOD activity, downregulated the expressions of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), upregulated expressions of organic anion transporter 1/3 (OAT1/3) and ATP-binding cassette transporter subfamily G member 2 (ABCG2) at both protein and mRNA levels, and suppressed the activation of the JAK2/STAT3 signaling pathway. In addition, BRB significantly decreased the levels of inflammatory mediators (IL-1β, IL-6, and TNF-α). In conclusion, our study indicated that BRB exerted anti-hyperuricemic effect, at least in part, via regulating the urate transporter expressions and suppressing the JAK2/STAT3 signaling pathway. BRB was believed to be promising for further development into a potential therapeutic agent for HUA treatment.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; Berberine; Blood Urea Nitrogen; Chemical and Drug Induced Liver Injury; Creatinine; Cytokines; Disease Models, Animal; Glucose Transport Proteins, Facilitative; Hyperuricemia; Hypoxanthine; Janus Kinase 2; Kidney Diseases; Male; Mice; Organic Anion Transport Protein 1; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Oxonic Acid; Protective Agents; Signal Transduction; STAT3 Transcription Factor; Uric Acid; Xanthine Oxidase

The study was designed to explore the effects of Withaferin A (WFA) on hyperuricemia-induced kidney injury and its action mechanism. Potassium oxonate (PO) was employed to establish the hyperuricemic mouse model. The pathological changes of renal tissue were evaluated by hematoxylin-eosin and masson trichrome staining. The levels of creatinine, blood urea nitrogen (BUN), uric acid (UA) and xanthine oxidase (XOD) were detected using corresponding commercial kits. Expressions of collagen-related and apoptosis-associated proteins in renal tissues were, respectively, evaluated by immunofluorescence and western blotting. Cell apoptosis was detected by TUNEL assay, and transporter expressions using western blotting. Followed by WFA, NRK-52E cells were treated with UA before evaluation of apoptosis and fibrosis. Results indicated that WFA ameliorated renal damage, improved kidney function, and decreased levels of creatinine, BUN, UA, and XOD in PO-induced hyperuricemic mice. Furthermore, WFA significantly prevented renal fibrosis and increased the expression of collagen-related proteins. Similarly, WFA markedly inhibited renal apoptosis, accompanied by changes of apoptosis-related proteins. Importantly, expression of transporters responsible for the secretion of organic anion transporter 1 (OAT1), OAT3, ATP-binding cassette subfamily G member 2 (ABCG2) was remarkably enhanced whereas that of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) was reduced in renal tissues of mice with hyperuricemia.

Topics: Animals; Apoptosis; Disease Models, Animal; Fibrosis; Hyperuricemia; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Oxonic Acid; Withanolides; Xanthine Oxidase

Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity.. To investigate the effect of API treatment in HN and to reveal its underlying mechanisms.. The mice with HN were induced by potassium oxonate intraperitoneally and orally administered for two weeks. The effects of API on renal function, inflammation, fibrosis, and uric acid (UA) metabolism in mice with HN were evaluated. The effects of API on urate transporters were further examined in vitro.. The mice with HN exhibited abnormal renal urate excretion and renal dysfunction accompanied by increased renal inflammation and fibrosis. In contrast, API reduced the levels of serum UA, serum creatinine (CRE), blood urea nitrogen (BUN) and renal inflammatory factors in mice with HN. Besides, API ameliorated the renal fibrosis via Wnt/β-catenin pathway suppression. Furthermore, API potently promoted urinary UA excretion and inhibited renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in mice with HN. In vitro, API competitively inhibited URAT1 and GLUT9 in a dose-dependent manner, with IC. API could effectively attenuate HN through co-inhibiting UA reabsorption and Wnt/β-catenin pathway, and thus it might be a potential therapy to HN.

Topics: Animals; Apigenin; beta Catenin; Creatinine; Dose-Response Relationship, Drug; Fibrosis; Glucose Transport Proteins, Facilitative; HEK293 Cells; Humans; Hyperuricemia; Kidney Diseases; Male; Mice; Nephritis; Organic Anion Transporters; Oxonic Acid; Uric Acid; Wnt Signaling Pathway

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.

Topics: Animals; Antioxidants; Ascorbic Acid; Fibrosis; Hyperuricemia; Inflammation; Kidney Diseases; Male; Oxonic Acid; Rats; Rats, Sprague-Dawley

Hyperuricemia is an independent risk factor for chronic kidney disease (CKD). Excessive uric acid (UA) level in the blood leads to hyperuricemic nephropathy (HN), which is characterized by glomerular hypertension, arteriolosclerosis and tubulointerstitial fibrosis. Fatty acid binding protein 4 (FABP4) is a potential mediator of inflammatory responses which contributes to renal interstitial fibrosis. However, the roles of FABP4 in HN remains unknown. In the study, a mouse model of HN induced by feeding a mixture of adenine and potassium oxonate, severe kidney injury and interstitial fibrosis, as well as the increased kidney-expressed FABP4 protein level were evident, accompanied by the activation of inflammatory responses. Oral administration of BMS309403, a highly selective FABP4 inhibitor, improved renal dysfunction, inhibited the mRNA level of KIM-1 and NGAL, as well as reduced the expression of proinflammatory cytokines and fibrotic proteins in the injured kidneys. BMS309403 treatment also inhibited the FABP4 activity and further suppressed the activation of JAK2-STAT3 and NF-kB P65 signaling pathways in the hyperuricemia-injured kidneys and UA-stimulated human tubular epithelial (HK-2) cells, respectively. In summary, our study for the first time demonstrated that FABP4 played a crucial role in kidney inflammation and fibrosis via the regulation of JAK2-STAT3 and NF-kB P65 pathways in HN mice. The results suggested that FABP4 inhibition might be a promising therapeutic strategy for HN.

Topics: Adenine; Animals; Biphenyl Compounds; Cytokines; Fatty Acid-Binding Proteins; Fibrosis; Hepatitis A Virus Cellular Receptor 1; Humans; Hyperuricemia; Janus Kinase 2; Kidney; Kidney Diseases; Lipocalin-2; Male; Mice; Mice, Inbred C57BL; Nephritis; Oxonic Acid; Pyrazoles; STAT3 Transcription Factor; Transcription Factor RelA

We tested whether melamine nephrotoxicity was exacerbated by urate (a typical component of renal stones in humans) in rats with hyperuricemiainduced by the uricase inhibitor, potassium oxonate (Oxo).. Rats were exposed to melamine or Oxo alone or combinations of melamine (200-400 mg/kg) and Oxo (200-600 mg/kg) for 3 consecutive days. Kidney injury was evaluated by renal biochemical functions, histomorphology, and lipid peroxidation. Kidney crystals were analyzed for their composition.. Nephrotoxicity was minimal in animals administered melamine or Oxo alone, but it was demonstrable in animals administered at least 800 mg/kg of the two compounds combined. All rats in the 400+600 (melamine+Oxo) and 400+400 mg/kg groups and 4 out of 6 in the 200+600 mg/kg group died within 3 days; no rat died in the 200+400 or 200+200 mg/kg group. Dose-dependent renal damage resembling clinical findings in affected patients was observed in rats administered the two compounds. Crystal composition determination revealed the existence of melamine and uric acid in the affected kidneys, resembling human stones.. Our findings suggest that uric acid plays a key role in melamine-related kidney injury in humans. Future studies should consider uric acid together with melamine when examining adverse effects in humans.

Topics: Animals; Disease Models, Animal; Hyperuricemia; Kidney Diseases; Lipid Peroxidation; Male; Oxonic Acid; Rats, Wistar; Triazines

Iridoid glycosides of Paederia scandens (IGPS) are an active component isolated from Chinese herb P. scandens (LOUR.) MERRILL (Rubiaceae). Uric acid nephropathy (UAN) is caused by excessive uric acid, which results in damage of kidney tissue via urate crystals deposition in the kidneys. This study aimed to investigate the protective effects of IGPS on UAN in rats induced by yeast and potassium oxonate. Treatment groups received different doses of IGPS and allopurinol (AP) daily for 35 days respectively. The results showed that treatment with IGPS significantly prevented the increases of uric acid in serum and the elevation of systolic blood pressure (SBP), attenuated renal tissue injury, improved renal function and reserved the biological activity of NOS-1. IGPS also inhibited the biological activity of TNF-α and TGF-β1, and suppressed the mRNA expressions of TNF-α and TGF-β1 in renal tissue. Taken together, the present and our previous findings suggest that IGPS exerts protective effects against kidney damage in UAN rats through its uric acid-lowering, anti-inflammatory and immunomodulatory properties. Furthermore, decreasing SBP by up regulation of NOS-1 expression and down regulation of TNF-α and TGF-β1 expression are involved in the effect of IGPS on high uric acid-induced nephropathy.

Topics: Animals; Base Sequence; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; DNA Primers; Hypertension; Iridoid Glycosides; Kidney Diseases; Male; Nitric Oxide Synthase; Oxonic Acid; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Rubiaceae; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Uric Acid; Yeasts