Pharmacologic targeting ERK1/2 attenuates the development and progression of hyperuricemic nephropathy in rats
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Na Liu1, Liuqing Xu1, Yingfeng Shi1, Lu Fang1, Hongwei Gu1, Hongrui Wang1, Xiaoqiang Ding2 and Shougang Zhuang1,3
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
2Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
3Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903, USA
Shougang Zhuang, email: [email protected]
Xiaoqiang Ding, email: [email protected]
Keywords: hyperuricemic nephropathy, ERK1/2, TGF-β/Smad signaling pathway, urate transporters, inflammation
Received: November 16, 2016 Accepted: February 20, 2017 Published: April 10, 2017
The pathogenesis of hyperuricemia-induced chronic kidney disease is largely unknown. In this study, we investigated whether extracellular signal–regulated kinases1/2 (ERK1/2) would contribute to the development of hyperuricemic nephropathy (HN). In a rat model of HN induced by feeding mixture of adenine and potassium oxonate, increased ERK1/2 phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, in parallel with diminished levels of renal function and increased urine microalbumin excretion. Administration of U0126, which is a selective inhibitor of the ERK1/2 pathway, improved renal function, decreased urine microalbumin and inhibited activation of renal interstitial fibroblasts as well as accumulation of extracellular proteins. U0126 also inhibited hyperuricemia-induced expression of multiple profibrogenic cytokines/chemokines and infiltration of macrophages in the kidney. Furthermore, U0126 treatment suppressed xanthine oxidase, which mediates uric acid production. It also reduced expression of the urate anion exchanger 1, which promotes reabsorption of uric acid, and preserved expression of organic anion transporters 1 and 3, which accelerate uric acid excretion in the kidney of hyperuricemic rats. Finally, U0126 inhibited phosphorylation of Smad3, a key mediator in transforming growth factor (TGF-β) signaling. In cultured renal interstitial fibroblasts, inhibition of ERK1/2 activation by siRNA suppressed uric acid-induced activation of renal interstitial fibroblasts. Collectively, pharmacologic targeting of ERK1/2 can alleviate HN by suppressing TGF-β signaling, reducing inflammation responses, and inhibiting the molecular processes associated with elevation of blood uric acid levels in the body. Thus, ERK1/2 inhibition may be a potential approach for the prevention and treatment of hyperuricemic nephropathy.
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