mulberroside-a and Hyperuricemia

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