Allopurinol, rutin, and quercetin attenuate hyperuricemia and renal dysfunction in rats induced by fructose intake: renal organic ion transporter involvement

Fructose consumption has been recently related to an epidemic of metabolic syndrome, and hyperuricemia plays a pathogenic role in fructose-induced metabolic syndrome. Fructose-fed rats showed hyperuricemia and renal dysfunction with reductions of the urinary uric acid/creatinine ratio and fractional excretion of uric acid (FEur), as well as other features of metabolic syndrome. Lowering serum uric acid levels with allopurinol, rutin, and quercetin increased the urinary uric acid/creatinine ratio and FEurand attenuated other fructose-induced metabolic abnormalities in rats, demonstrating that hyperuricemia contributed to the deficiency of renal uric acid excretion in this model. Furthermore, we found that fructose upregulated the expression levels of rSLC2A9v2 and renal-specific transporter (rRST), downregulated the expression levels of organic anion transporters (rOAT1 and rUAT) and organic cation transporters (rOCT1 and rOCT2), with the regulators prostaglandin E2(PGE2) elevation and nitric oxide (NO) reduction in rat kidney. Allopurinol, rutin, and quercetin reversed dysregulations of these transporters with PGE2reduction and NO elevation in the kidney of fructose-fed rats. These results suggested that dysregulations of renal rSLC2A9v2, rRST, rOAT1, rUAT, rOCT1, and rOCT2 contributed to fructose-induced hyperuricemia and renal dysfunction. Therefore, these renal transporters may represent novel therapeutic targets for the treatment of hyperuricemia and renal dysfunction in fructose-induced metabolic syndrome.

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Morin Improves Urate Excretion and Kidney Function through Regulation of Renal Organic Ion Transporters in Hyperuricemic Mice

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3q30h ◽

2010 ◽

Vol 13 (3) ◽

pp. 411 ◽

Cited By ~ 16

Author(s):

Cai-Ping Wang ◽

Xing Wang ◽

Xian Zhang ◽

Yun-Wei Shi ◽

Lei Liu ◽

...

Keyword(s):

Uric Acid ◽

Renal Dysfunction ◽

Glucose Transporter ◽

Organic Anion ◽

Fractional Excretion ◽

Organic Anion Transporter ◽

Mrna Levels ◽

Ion Transporters ◽

Beneficial Effects ◽

Anion Transporter

Purpose. Morin (3,5,7,2′,4′-pentahydroxyflavone), a plant-derived ﬂavonoid, has beneficial effects in animals with various diseases including hyperuricemia and renal dysfunction. Since the decreased renal excretion of uric acid is the hallmark of hyperuricemia and renal dysfunction, here we studied the effects of oral morin administration on renal organic ion transporters in oxonate-induced hyperuricemic mice. Methods. The hyperuricemia in mice was induced by potassium oxonate. Uric acid and creatinine concentrations in urine and serum, and fractional excretion of uric acid (FEUA) were performed to evaluate urate handling. Changes in the expression levels of renal organic ion transporters were detected by Western blotting and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Results. Morin treatment significantly reduced urinary uric acid/creatinine ratio and FEUA, resulting in the reduction of serum uric acid levels in hyperuricemic mice. And kidney dysfunction was also improved after morin treatment in this model. Protein and mRNA levels of renal glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1) were significantly decreased, and renal organic anion transporter (mOAT1) levels were remarkably increased in morin-treated hyperuricemic mice. Morin treatment also blocked down-regulation of renal organic cation and carnitine transporters (mOCT1, mOCT2, mOCTN1 and mOCTN2) in hyperuricemic mice. Conclusion. These results suggest that morin exhibits uricosuric effect via suppressing urate reabsorption and promoting urate secretion in the kidney of hyperuricemic mice and may help to attenuate deleterious effects of hyperuricemia with renal dysfunction.

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Serum Uric Acid to Creatinine Ratio as a Predictor of Metabolic Syndrome in Healthy Adults Men

Korean Journal of Clinical Laboratory Science ◽

10.15324/kjcls.2019.51.1.42 ◽

2019 ◽

Vol 51 (1) ◽

pp. 42-49

Author(s):

Myong Soo Kim ◽

Kyung A Shin

Keyword(s):

Metabolic Syndrome ◽

Uric Acid ◽

Serum Uric Acid ◽

Healthy Adults ◽

Creatinine Ratio

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The Association Between the Serum Uric Acid to Creatinine Ratio and Metabolic Syndrome, Liver Function, and Alcohol Intake in Healthy Japanese Subjects

Metabolic Syndrome and Related Disorders ◽

10.1089/met.2019.0024 ◽

2019 ◽

Vol 17 (7) ◽

pp. 380-387 ◽

Cited By ~ 3

Author(s):

Kengo Moriyama

Keyword(s):

Metabolic Syndrome ◽

Uric Acid ◽

Liver Function ◽

Serum Uric Acid ◽

Alcohol Intake ◽

Creatinine Ratio ◽

Japanese Subjects

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Serum uric acid to creatinine ratio is a useful predictor of renal dysfunction among diabetic persons

Diabetes & Metabolic Syndrome Clinical Research & Reviews ◽

10.1016/j.dsx.2019.04.023 ◽

2019 ◽

Vol 13 (3) ◽

pp. 1851-1856 ◽

Cited By ~ 2

Author(s):

Ryuichi Kawamoto ◽

Daisuke Ninomiya ◽

Asuka Kikuchi ◽

Taichi Akase ◽

Yoshihisa Kasai ◽

...

Keyword(s):

Uric Acid ◽

Renal Dysfunction ◽

Serum Uric Acid ◽

Creatinine Ratio

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Hypouricemic Effects of Chrysanthemum indicum L. and Cornus officinalis on Hyperuricemia-Induced HepG2 Cells, Renal Cells, and Mice

Plants ◽

10.3390/plants10081668 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1668

Author(s):

Ok-Kyung Kim ◽

Jeong-Moon Yun ◽

Minhee Lee ◽

Dakyung Kim ◽

Jeongmin Lee

Keyword(s):

Uric Acid ◽

Hepg2 Cells ◽

Glucose Transporter ◽

Organic Anion ◽

Organic Anion Transporter ◽

Expression Levels ◽

Cornus Officinalis ◽

Anion Transporter ◽

Chrysanthemum Indicum ◽

Primary Mouse

Hyperuricemia, abnormally excess accumulation of uric acid, is caused by an imbalance between the production and excretion of uric acid and is a major cause of gout. We compared the effects of extracts from Chrysanthemum indicum L. (Ci) and Cornus officinalis Siebold and Zucc. (Co) on hyperuricemia, both individually and in combination (FSU-CC), using hypoxanthine-treated human liver cancer (HepG2) cells, primary mouse renal proximal tubule cells, and potassium oxonate induced hyperuricemic mice. The Ci contained 7.62 mg/g luteolin and 0 mg/g loganin, Co contained 0 mg/g luteolin and 4.90 mg/g loganin, and FSH-CC contained 3.95 mg/g luteolin and 2.48 mg/g loganin. We found that treatment with Ci, Co, and FSU-CC suppressed the activity of xanthine oxidase and mRNA expression of xanthine dehydrogenase while inducing an increase in the expression levels of the organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) proteins and a decrease in the expression levels of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) proteins. Particularly, treatment and supplementation with FSU-CC showed stronger effects than those of supplementation with either Ci or Co alone. We observed that the excretion of creatinine and uric acid in the combination of Ci and Co was higher than that observed in their individual supplementations and was similar to that of the normal group. Therefore, our data suggest that a combination of Ci and Co may potentially be used for the development of effective natural anti-hyperuricemic functional foods.

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Pharmacologic Targeting of BET Proteins Attenuates Hyperuricemic Nephropathy in Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.636154 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chongxiang Xiong ◽

Jin Deng ◽

Xin Wang ◽

Xiaofei Shao ◽

Qin Zhou ◽

...

Keyword(s):

Uric Acid ◽

Epithelial To Mesenchymal Transition ◽

Organic Anion ◽

Mesenchymal Cell ◽

Serum Levels ◽

Organic Anion Transporter ◽

Vimentin Expression ◽

Mesenchymal Transition ◽

Expression Levels ◽

Anion Transporter

Hyperuricemia is an independent risk factor for renal damage and promotes the progression of chronic kidney disease. In this study, we investigated the effect of I-BET151, a small-molecule inhibitor targeting the bromodomain and extraterminal (BET) proteins, on the development of hyperuricemic nephropathy (HN), and the mechanisms involved. Expression levels of bromodomain-containing protein 2 and 4, but not 3 were increased in the kidney of rats with HN; administration of I-BET151 effectively prevented renal dysfunction, decreased urine microalbumin, and attenuated renal fibrosis as indicated by reduced activation of renal interstitial fibroblasts and expression of fibronectin and collagen I in HN rats. Mechanistic studies show that I-BET151 treatment inhibited transition of renal epithelial cells to a mesenchymal cell type as evidenced by preservation of E-cadherin and reduction of vimentin expression. This was coincident with reduced expression of TGF-β1 and dephosphorylation of Smad3 and ERK1/2. I-BET151 was also effective in inhibiting phosphorylation of NF-κB, expression of multiple cytokines and chemokines, and infiltration of macrophages to the injured kidney. Although there were increased serum levels of uric acid and xanthine oxidase, an enzyme that catalyzes production of uric acid, and decreased expression of renal organic anion transporter 1 and 3 that promote urate excretion in the model of HN, and reduced expression levels of urine uric acid, I-BET151 treatment did not affect these responses. Collectively, our results indicate that I-BET151 alleviates HN by inhibiting epithelial to mesenchymal transition and inflammation in association with blockade of TGF-β, ERK1/2 and NF-κB signaling.

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Hypouricemic and Anti-oxidant Effects of Chrysanthemum indicum L. and Cornus officinalis In Vitro and In Vivo Models

10.21203/rs.3.rs-723565/v1 ◽

2021 ◽

Author(s):

Ok-kyung Kim ◽

Jeong Moon Yun ◽

Minhee Lee ◽

Dakyung Kim ◽

Jeongmin Lee

Keyword(s):

Uric Acid ◽

Organic Anion ◽

Organic Anion Transporter ◽

In Vivo Models ◽

Expression Levels ◽

Cornus Officinalis ◽

Anion Transporter ◽

Chrysanthemum Indicum

Abstract Background: Hyperuricemia, abnormally excess accumulation of uric acid, is caused by an imbalance between the production and excretion of uric acid and is a major cause of gout. We compared the effects of extracts from Chrysanthemum indicum L. (Ci) and Cornus officinalis Siebold & Zucc (Co) on hyperuricemia, both individually and in combination (FSU-CC), Methods: We used hypoxanthine-treated human liver cancer (HepG2) cells and primary mouse renal proximal tubule cells for in vitro model, and potassium oxonate-induced hyperuricemic mice for in vivo model.Results: We found that treatment of Ci, Co, and FSU-CC suppressed the activity of xanthine oxidase and mRNA expression of xanthine dehydrogenase, while inducing an increase in the expression levels of the organic anion transporter 1 and organic anion transporter 3 proteins and a decrease in the expression levels of glucose transporter 9 and urate transporter 1 proteins. Particularly, treatment and supplementation with FSU-CC showed stronger effects than those of supplementation with either Ci or Co alone. We observed that the excretion of creatinine and uric acid in the combination of Ci and Co was higher than that observed in their individual supplementations and was similar to that of the normal group.Conclusions: Therefore, our data suggest that a combination of Ci and Co may potentially be used for the development of effective natural anti-hyperuricemic functional foods.

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