The Protective Effects Of Quercetin And Its Molecular Mechanisms On Kidney Injury In STZ-induced Diabetic Rats

Diabetic nephropathy is the leading cause of chronic renal disease.It also is a major cause of cardiovascular mortality.Studies on the pathogenesis of diabetic nephropathy,and corresponding drug treatment are great significance to delay or prevent the harmfulness.Inflammation is suggested to play an important role in the onset of diabetic nephropathy.Recently,the NOD-like receptor 3(NLRP3)inflammasome has been recognized as a causal factor of the development of kidney injury.Both uric acid and lipid are considered as danger signals in the NLRP3 inflammasome activation.In this study,streptozotocin(STZ)was used to induce diabetic nephropathy in rats,accompanying hyperuricemia and dyslipidemia.The present study found that the inflammasome components NLRP3,apoptosis-associated speck-like protein and Caspase-1 were over-expressed in the kidney of diabetic rats.Elevations of renal interleukin 1?(IL-1?)and IL-18 were also observed in this model,which may subsequently participate in renal injury process.These results suggest that the activation of renal NLRP3 inflammasome may involve in the development of diabetic nephropathy in rats.Quercetin,a naturally occurring polyphenolic flavonoid compound,is widespread components of anti-diabetic drugs and food.In addition,it exhibited kinds of bioactivities including hypouricemic action,lowing serum lipid,antioxidant and anti-inflammatory activity,and renal protection.In this study,quercetin and allopurinol(an inhibitor of uric acid generation commonly used in clinical)were confirmed to enhance renal urate excretion and then improve hyperuricemia by regulating renal urate transport-related proteins including organic anion transporters 1(rOATl),rOAT2,rOAT3,electrogenic urate transporter(rUAT),glucose transporter 9(rGLUT9)and renal-specific transporter(rRST)in diabetic rats.They also improved renal lipid disorder by regulating lipid metabolism-related genes including renal peroxisome proliferator-activated receptor ?(PPAR-?),organic cation/canitine transporter 2(OCTN2),carnitine palmitoyltransferase-1(CPT-1)and phosphorylation of acetyl-CoA carboxylase 2(ACC2)in diabetic rats.Moreover,quercetin and allopurinol were found to inhibit the activation of renal NLRP3 inflammasome,alleviate the NLRP3 inflammasome-driven inflammatory response to delay the process of diabetic nephropathy,exhibiting renal protection.These observations provide the basis for exploring the new pathogenesis of diabetic nephropathy and preventing diabetic nephropathy by urate-lowering agents.