stilbenes and Hyperuricemia

Previous studies have disclosed the antihyperuricemic effect of polydatin, a natural precursor of resveratrol; however, the mechanisms of action still remain elusive. The present study was undertaken to evaluate the therapeutic effects and the underlying mechanisms of polydatin on potassium oxonate-induced hyperuricemia in rats through metabonomic technology from a holistic view. Nuclear magnetic resonance (NMR) spectroscopy was applied to capture the metabolic changes in sera and urine collected from rats induced by hyperuricemia and polydatin treatment. With multivariate data analysis, significant metabolic perturbations were observed in hyperuricemic rats compared with the healthy controls. A total of eleven and six metabolites were identified as differential metabolites related to hyperuricemia in serum and urine of rats, respectively. The proposed pathways primarily included branched-chain amino acid (BCAA) metabolism, glycolysis, the tricarboxylic acid cycle, synthesis and degradation of ketone bodies, purine metabolism, and intestinal microflora metabolism. Additionally, some metabolites indicated the risk of renal injury induced by hyperuricemia. Polydatin significantly lowered the levels of serum uric acid, creatinine, and blood urea nitrogen and alleviated the abnormal metabolic status in hyperuricemic rats by partially restoring the balance of the perturbed metabolic pathways. Our findings shed light on the understanding of the pathophysiological process of hyperuricemia and provided a reference for revealing the metabolic mechanism produced by polydatin in the treatment of hyperuricemia.

Topics: Animals; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Drugs, Chinese Herbal; Glucosides; Humans; Hyperuricemia; Kidney; Male; Metabolomics; Oxonic Acid; Rats; Rats, Sprague-Dawley; Stilbenes; Uric Acid

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.

Topics: Animals; Blueberry Plants; Creatinine; Disease Models, Animal; Drugs, Chinese Herbal; Fibronectins; Fibrosis; Hyperuricemia; Kidney; Kidney Diseases; Kidney Function Tests; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Smad3 Protein; Stilbenes; Transforming Growth Factor beta1; Uric Acid

Topics: AMP-Activated Protein Kinases; Animals; Glucosides; Humans; Hyperuricemia; Inflammasomes; Kidney; Male; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxonic Acid; Rats; Rats, Sprague-Dawley; Sirtuin 1; Stilbenes

This study established a hyperuricemic rat model to elucidate the effect of resveratrol on the transport of UA in the kidney.. Hyperuricemia was induced in rats through daily oral gavage of a potassium oxonate and UA mixture over 3 weeks. Our results revealed that resveratrol significantly reduced the serum UA levels but not creatinine, c-creative protein, alanine aminotransferase, or aspartate aminotransferase levels in these rats. Furthermore, renal URAT1 and OAT1 mRNA expression were significantly higher in the rats treated with allopurinol than in those with no treatment. Therefore, allopurinol not only inhibited UA production but also mediated renal URAT1 and OAT1 expression. The correlation analysis revealed that UA levels correlated negatively with renal IL-6 mRNA expression in rats treated with allopurinol. Moreover, URAT1 showed strong immunoreactivity in the distal convoluted tubule of rats treated with allopurinol or resveratrol and in hyperuricemic treated with allopurinol. Finally, in the rats treated with resveratrol, UA levels correlated negatively with renal URAT1 mRNA expression; thus, resveratrol reduced URAT1 mRNA expression under high UA levels, thereby reducing UA reabsorption in renal cells.. Resveratrol contributes to URAT1 expression, which is potentially useful in therapeutic strategies aimed at treating hyperuricemia.

Topics: Alanine Transaminase; Allopurinol; Animals; Anion Transport Proteins; Aspartate Aminotransferases; C-Reactive Protein; Creatinine; Cytokines; Disease Models, Animal; Hyperuricemia; Kidney; Male; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Messenger; Stilbenes; Uric Acid

Topics: Animals; Anti-Inflammatory Agents; Dipterocarpaceae; Humans; Hyperuricemia; Interleukin-18; Interleukin-1beta; Interleukin-6; Kidney; Male; Mice; Organic Anion Transport Protein 1; Plant Extracts; Stilbenes; Tumor Necrosis Factor-alpha; Uric Acid

Silent information regulator T1 (SIRT1) plays several key roles in the regulation of lipid and glucose homoeostasis. In this study, we investigated the potential role of SIRT1 in hyperuricemia and explored possible mechanisms. Significant hyperuricemia was detected in C57BL/6 mice treated with oxonate and yeast polysaccharide. Resveratrol (RSV), a specific SIRT1 activator, was administered to the mice. SIRT1 suppressed the increased serum uric acid level but up-regulated the expression of urate transporter ATP-binding cassette subfamily G member 2 (ABCG2) in the ileum of hyperuricemic mice. In a human colon carcinoma cell line, SIRT1 promoted ABCG2 production through the deacetylation of peroxisome proliferator-activated receptor (PPAR) γ co-activator 1α (PGC-1α), which then activated the effectors of PPARγ. Interestingly, the SIRT1-induced up-regulation of ABCG2 was significantly inhibited when PGC-1α or PPARγ was blocked by siRNA transfection. Our data demonstrated that SIRT1 and its activator, RSV, have clear anti-hyperuricemia functions in this mouse model. One possible mechanism is the activation of ABCG2 in the ileum through the PGC-1α/PPARγ pathway.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; Cell Line, Tumor; Humans; Hyperuricemia; Ileum; Mice; Neoplasm Proteins; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Uric Acid

Hyperuricemia mice model was established with uricase inhibitor (potassium oxonate) and uric acids in serum were observed. Polydatin (5, 10, 20 mg · kg(-1)) and benzbromarone (16.7 mg · kg(-1)) were given ig for 7 d in mice. Kidney tissues were used to detect gene contents ofurate anion transporter 1 (URAT1), organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) by real-time-PCR. The results showed that polydatin and benzbromarone can significantly reduce uric acid in blood of hyperuricemia mice (P < 0.05), compared with the model group. URAT1, OAT1 and OAT3 contents of the kidney in hyperuricemia mice changed significantly (P < 0.05), compared with the blank group. Polydatin can significantly inhibit the changing trends in these genes induced by potassium oxonate in a dose-dependent manner, the difference was significant (P < 0.05), compared with the model group. Those indicated that polysatin could reduce the level of the serum uric acid through promoting uric acid excretion.

Topics: Animals; Disease Models, Animal; Glucosides; Hyperuricemia; Kidney; Mice; Stilbenes; Uric Acid

Stilbenes, of which, resveratrol is a representative compound in foods and plants, possess a variety of bioactivities including antioxidation, anti-inflammation, chemoprevention, and cardioprotection. This study was conducted to evaluate the antihyperuricemic and nephroprotective effects of resveratrol and its analogues and explore the possible mechanisms. The structure-activity relationships were analyzed.. Potassium oxonate-induced hyperuricemic mice were dosed by gavage with eight stilbenes. Uric acid, creatinine, and blood urea nitrogen (BUN) levels in serum and urine, clearance rate of creatinine and BUN, 24-h urate excretion, and fractional excretion of uric acid, uromodulin levels in urine and kidney were determined to evaluate renal urate handling and function. Renal protein levels of organic ion transporters were detected to elucidate the possible mechanisms. Resveratrol, trans-4-hydroxystilbene, pterostilbene, polydatin, and mulberroside A were found to have antihyperuricemic activities. These compounds together with trans-2-hydroxystilbene provided nephroprotection. Trans-3,4',5-trimethoxystilbene and cis-combretastatin A-4 had no effects.. The uricosuric and nephroprotective actions of resveratrol and its analogues were mediated by regulating renal organic ion transporters in hyperuricemic mice, supporting their beneficial effects for the prevention of hyperuricemia. The number and position, methoxylation and glycosylation of hydroxyl groups in these trans-stilbenes were required for their effects.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Blood Urea Nitrogen; Carrier Proteins; Creatinine; Disaccharides; Gene Expression Regulation; Glucose Transport Proteins, Facilitative; Glucosides; Gout Suppressants; Hyperuricemia; Kidney; Male; Membrane Proteins; Mice; Mice, Inbred Strains; Octamer Transcription Factor-1; Organic Anion Transport Protein 1; Organic Anion Transporters; Organic Cation Transport Proteins; Organic Cation Transporter 2; Oxonic Acid; Resveratrol; Solute Carrier Family 22 Member 5; Stilbenes; Symporters; Uric Acid

Mulberroside A is a major stilbene glycoside of MORUS ALBA L. (Moraceae), which is effectively used for the treatment of hyperuricemia and gout in traditional Chinese medicine. We examined whether mulberroside A had effects on renal urate underexcretion and dysfunction in oxonate-induced hyperuricemic mice and investigated the potential uricosuric and nephroprotective mechanisms involved. Mulberroside A at 10, 20, and 40 mg/kg decreased serum uric acid levels and increased urinary urate excretion and fractional excretion of uric acid in hyperuricemic mice. Simultaneously, it reduced serum levels of creatinine and urea nitrogen (10-40 mg/kg), urinary N-acetyl- β-D-glucosaminidase activity (10-40 mg/kg), β₂-microglobulin (10-40 mg/kg) and albumin (20-40 mg/kg), and increased creatinine clearance (10-40 mg/kg) in hyperuricemic mice. Furthermore, mulberroside A downregulated mRNA and protein levels of renal glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1), and upregulated mRNA and protein levels of renal organic anion transporter 1 (mOAT1) and organic cation and carnitine transporters (mOCT1, mOCT2, mOCTN1, and mOCTN2) in hyperuricemic mice. This is the first study demonstrating that mulberroside A exhibits uricosuric and nephroprotective effects mediated in part by cooperative attenuation of the expression alterations of renal organic ion transporters in hyperuricemic mice. These data suggest that mulberroside A may be a new drug candidate for the treatment of hyperuricemia with renal dysfunction.

Topics: Acetylglucosaminidase; Albuminuria; Animals; beta 2-Microglobulin; Blood Urea Nitrogen; Carrier Proteins; Creatinine; Disaccharides; Drugs, Chinese Herbal; Glucose Transport Proteins, Facilitative; Hyperuricemia; Kidney; Kidney Diseases; Male; Membrane Proteins; Mice; Morus; Organic Anion Transport Protein 1; Organic Anion Transporters; Organic Cation Transport Proteins; Organic Cation Transporter 2; Protective Agents; Solute Carrier Family 22 Member 5; Stilbenes; Symporters; Uric Acid; Uricosuric Agents