Abstract
Renal interstitial fibrosis is a common pathway for the progression of chronic kidney disease (CKD) to end-stage renal disease. Renalase, acting as a signaling molecule, has been reported to have cardiovascular and renal protective effects. However, its role in renal fibrosis remains unknown. In this study, we evaluated the therapeutic efficacy of renalase in rats with complete unilateral ureteral obstruction (UUO) and examined the inhibitory effects of renalase on transforming growth factor-β1 (TGF-β1)-induced epithelial–mesenchymal transition (EMT) in human proximal renal tubular epithelial (HK-2) cells. We found that in the UUO model, the expression of renalase was markedly downregulated and adenoviral-mediated expression of renalase significantly attenuated renal interstitial fibrosis, as evidenced by the maintenance of E-cadherin expression and suppressed expression of α-smooth muscle actin (α-SMA), fibronectin and collagen-I. In vitro, renalase inhibited TGF-β1-mediated upregulation of α-SMA and downregulation of E-cadherin. Increased levels of Phospho-extracellular regulated protein kinases (p-ERK1/2) in TGF-β1-stimulated cells were reversed by renalase cotreatment. When ERK1 was overexpressed, the inhibition of TGF-β1-induced EMT and fibrosis mediated by renalase was attenuated. Our study provides the first evidence that renalase can ameliorate renal interstitial fibrosis by suppression of tubular EMT through inhibition of the ERK pathway. These results suggest that renalase has potential renoprotective effects in renal interstitial fibrosis and may be an effective agent for slowing CKD progression.
Highlights
It is generally recognized that the incidence of chronic kidney disease (CKD) is increasing worldwide and is a public health problem posing a serious threat to human health
Accumulating evidence suggests that epithelial–mesenchymal transition (EMT) of tubular epithelial cells contributes significantly to the onset and pathogenesis of Renal interstitial fibrosis (RIF) [2]
We examined the anti-fibrosis effects of renalase in vivo in a rat model of tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO) and in vitro in EMT of human proximal tubular epithelial cells induced by transforming growth factor-β1 (TGF-β1)
Summary
It is generally recognized that the incidence of chronic kidney disease (CKD) is increasing worldwide and is a public health problem posing a serious threat to human health. Renal interstitial fibrosis (RIF), characterized by excessive deposition of extracellular matrix, is recognized as a common pathological feature of CKD which leads to the development of end-stage renal disease (ESRD), accompanied by progression of renal dysfunction [1]. Accumulating evidence suggests that epithelial–mesenchymal transition (EMT) of tubular epithelial cells contributes significantly to the onset and pathogenesis of RIF [2]. Of the many factors that trigger EMT, transforming growth factor-β1 (TGF-β1) is considered to be the most potent inducer of EMT in various types of epithelial cells via both Smad-dependent and -independent mechanisms [4]. Targeting TGF-β1-mediated EMT may ameliorate RIF and the progressive loss of renal function
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