Abstract
Background: The pivotal role of transforming growth factor-β1 (TGF-β1)-induced tubulointerstitial fibrosis in the progression of chronic kidney disease is an active topic of research. Recent evidence indicates that hyperuricemia is associated with increased TGF-β1 and progressive tubulointerstitial injury. We examined the hypothesis that lowering serum uric acid attenuates TGF-β1-induced profibrogenic tubular change in type 2 diabetic nephropathy. Methods: KK-Ay/Ta mice, an animal model of type 2 diabetes, were provided access to either regular drinking water or drinking water containing 10 mg/dl of allopurinol. Normal rat kidney epithelial cells were cultured and stimulated with 5 m<smlcap>M</smlcap> uric acid with or without allopurinol. Results: Type 2 diabetic mice that received allopurinol exhibited smaller increases in urinary albumin:creatinine ratio than diabetic control mice, as well as attenuated TGF-β1 and Smad pathway-induced profibrogenic tubular changes in diabetic kidneys. Allopurinol attenuated TGF-β1-induced Smad pathway activation in tubular cells. These findings were related to increases in E-cadherin, and decreases in vimentin and α-smooth muscle actin. Uric acid-induced upregulation of TGF-β1 depends on mitogen-activated protein kinase signaling. Conclusions: This is the first study to demonstrate that reducing serum uric acid has preventive effects against to profibrogenic progression in type 2 diabetic kidney disease. These findings suggest that lowering serum uric acid may be an effective therapeutic intervention to prevent the progression of type 2 diabetic kidney disease.
Journal Section:
Original Paper
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