IGF-1 protects tubular epithelial cells during injury via activation of ERK/MAPK signaling pathway

Lei Niu,Shuming Pan,Yang Yu,Aihua Fei,Zengbin Wu

doi:10.1038/srep28066

Abstract

Injury of renal tubular epithelial cells can induce acute renal failure and obstructive nephropathy. Previous studies have shown that administration of insulin-like growth factor-1 (IGF-1) ameliorates the renal injury in a mouse unilateral ureteral obstruction (UUO) model, whereas the underlying mechanisms are not completely understood. Here, we addressed this question. We found that the administration of IGF-1 significantly reduced the severity of the renal fibrosis in UUO. By analyzing purified renal epithelial cells, we found that IGF-1 significantly reduced the apoptotic cell death of renal epithelial cells, seemingly through upregulation of anti-apoptotic protein Bcl-2, at protein but not mRNA level. Bioinformatics analyses and luciferase-reporter assay showed that miR-429 targeted the 3′-UTR of Bcl-2 mRNA to inhibit its protein translation in renal epithelial cells. Moreover, IGF-1 suppressed miR-429 to increase Bcl-2 in renal epithelial cells to improve survival after UUO. Furthermore, inhibition of ERK/MAPK signaling pathway in renal epithelial cells abolished the suppressive effects of IGF-1 on miR-429 activation, and then the enhanced effects on Bcl-2 in UUO. Thus, our data suggest that IGF-1 may protect renal tubular epithelial cells via activation of ERK/MAPK signaling pathway during renal injury.

Highlights

Obstructive nephropathy is a major cause of renal failure, the cellular and molecular mechanisms of which have been elucidated in the past years
Insulin-like growth factor-1 (IGF-1) is a peptide growth factor produced by the collecting duct of the adult kidney, and its receptors are present in glomeruli and on the basolateral membrane of renal proximal tubular cells
By analyzing purified renal epithelial cells, we found that IGF-1 significantly reduced the apoptotic cell death of renal epithelial cells, seemingly through upregulation of anti-apoptotic protein B-cell lymphoma 2 (Bcl-2)

Summary

Introduction

Obstructive nephropathy is a major cause of renal failure, the cellular and molecular mechanisms of which have been elucidated in the past years. Fibroblasts transform to myofibroblasts that induce excess deposition of the extracellular matrix in response to the cytokines, chemokines and other signaling molecules secreted by tubular and interstitial cells[5,6,7,8] Among these biological steps, injury and apoptotic cell death of renal epithelial cells are the initial process. The administration of exogenous IGF-1 has been shown to accelerate recovery from ischemic acute renal failure, possible through enhanced proliferation and reduced apoptosis of tubular epithelial cells[12]. Bioinformatics analyses and luciferase-reporter assay showed that miR-429 targeted the 3′-UTR of Bcl-2 mRNA to inhibit its protein translation in renal epithelial cells. Inhibition of ERK/ MAPK signaling pathway in renal epithelial cells abolished the suppressive effects of IGF-1 on miR-429 activation, and the enhanced effects on Bcl-2 in UUO

Methods

Results

Conclusion