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-A(y)/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 mM 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.
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-A(y)/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 mM uric acid with or without allopurinol. RESULTS: Type 2 diabeticmice 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.
Authors: Petter Bjornstad; David M Maahs; Carlos A Roncal; Janet K Snell-Bergeon; Viral N Shah; Tamara Milagres; Samuel L Ellis; Matthew Hatch; Linh T Chung; Marian J Rewers; Satish Garg; David Z Cherney; Laura Pyle; Kristen J Nadeau; Richard J Johnson Journal: Diabetes Obes Metab Date: 2018-03-24 Impact factor: 6.577
Authors: Petter Bjornstad; Carlos Roncal; Tamara Milagres; Laura Pyle; Miguel Angel Lanaspa; Franziska K Bishop; Janet K Snell-Bergeon; Richard J Johnson; R Paul Wadwa; David M Maahs Journal: Pediatr Nephrol Date: 2015-12-23 Impact factor: 3.714