Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation.
Hyperuricemia, hyperlipidemia and inflammation are associated with diabetic nephropathy. The NLRP3 inflammasome-mediated inflammation is recently recognized in the development of kidney injury. Urate and lipid are considered as danger signals in the NLRP3 inflammasome activation. Although dietary flavonoid quercetin and allopurinol alleviate hyperuricemia, dyslipidmia and inflammation, their nephroprotective effects are currently unknown. In this study, we used streptozotocin (STZ)-induced diabetic nephropathy model with hyperuricemia and dyslipidemia in rats, and found over-expression of renal inflammasome components NLRP3, apoptosis-associated speck-like protein and Caspase-1, resulting in elevation of IL-1β and IL-18, with subsequently deteriorated renal injury. These findings demonstrated the possible association between renal NLRP3 inflammasome activation and lipid accumulation to superimpose causes of nephrotoxicity in STZ-treated rats. The treatment of quercetin and allopurinol regulated renal urate transport-related proteins to reduce hyperuricemia, and lipid metabolism-related genes to alleviate kidney lipid accumulation in STZ-treated rats. Furthermore, quercetin and allopurinol were found to suppress renal NLRP3 inflammasome activation, at least partly, via their anti-hyperuricemic and anti-dyslipidemic effects, resulting in the amelioration of STZ-induced the superimposed nephrotoxicity in rats. These results may provide a basis for the prevention of diabetes-associated nephrotoxicity with urate-lowering agents such as quercetin and allopurinol.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China.
Chuang
C
Wang
Ying
Y
Pan
Qing-Yu
QY
Zhang
Fu-Meng
FM
Wang
Ling-Dong
LD
Kong
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D000493:Allopurinol / Q000494:pharmacology* / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D001835:Body Weight; D002352:Carrier Proteins; D003404:Creatinine / Q000652:urine; D017931:DNA Primers / Q000235:genetics; D003928:Diabetic Nephropathies / Q000150:complications*; D005786:Gene Expression Regulation / Q000187:drug effects*; D058847:Inflammasomes / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009929:Organ Size; D011794:Quercetin / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013311:Streptozocin; D014527:Uric Acid / Q000097:blood / Q000652:urine
D002352:Carrier Proteins; D017931:DNA Primers; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D014527:Uric Acid; D013311:Streptozocin; D000493:Allopurinol; D011794:Quercetin; D003404:Creatinine