Reducing Serum Uric Acid Attenuates TGF-β₁-Induced Profibrogenic Progression in Type 2 Diabetic Nephropathy

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-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 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.

Linking uric acid metabolism to diabetic complications

“…Febuxostat has a higher renoprotective effect than allopurinol, inhibits oxidative stress, has anti-atherogenic activity, reduces blood pressure, and decreases pulse wave velocity and left ventricular mass index, most likely due to a strong SUA lowering effect [65] . In an animal diabetic nephropathy model, allopurinol attenuated transforming growth factor-beta1-induced Smad pathway activation in tubular cells [66] .…”

EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy

“…Signaling Pathway in the Kidney of Hyperuricemic Rats TGF-b signaling contributes to HN, 52 but whether EGFR mediates uric acid-induced activation of TGF-b signaling remains unclear. To address this issue, we first examined the effect of EGFR inhibition on the production of TGF-b in the kidney of HN rats by ELISA.…”

The Role of Uric Acid in Kidney Fibrosis: Experimental Evidences for the Causal Relationship

“…The mechanism for protection was shown to be due to a reduction in inflammatory cells mediated by a reduction in ICAM-1 expression by tubular epithelial cells [37]. In another diabetic nephropathy model using KK-A(y)Ta mice, lowering UA levels with allopurinol attenuated transforming growth factor- (TGF-) β 1-induced profibrogenic progression in the mice, suggesting that lowering serum UA may be an effective therapeutic intervention to prevent the progression of diabetic nephropathy [38]. …”

“…Thereafter, the research was performed using animal models of various kidney disease conditions, such as CsA nephropathy [36], diabetic nephropathy [38, 51], obstructive nephropathy [61], ischemia-reperfusion injury [62], and 5/6 nephrectomy rat model [34]. Further research using diverse animal models of CKD [79, 80] is essential not only for gaining a better understanding of molecular mechanisms of kidney fibrosis but also for designing more appropriate clinical studies.…”