Proinsulin C-peptide antagonizes the profibrotic effects of TGF-β1 via up-regulation of retinoic acid and HGF-related signaling pathways

Hills, Claire E. and Willars, Gary B. and Brunskill, Nigel J. (2010) Proinsulin C-peptide antagonizes the profibrotic effects of TGF-β1 via up-regulation of retinoic acid and HGF-related signaling pathways. Molecular Endocrinology, 24 (4). pp. 822-831. ISSN 0888-8809

Full content URL: http://dx.doi.org/10.1210/me.2009-0391

Full text not available from this repository.

Item Type:Article
Item Status:Live Archive

Abstract

Novel signaling roles for C-peptide have recently been discovered with evidence that it can ameliorate complications of type 1 diabetes. Here we sought to identify new pathways regulated by C-peptide of relevance to the pathophysiology of diabetic nephropathy. Microarray analysis was performed to identify genes regulated by either C-peptide and/or TGF-β1 in a human proximal tubular cell line, HK-2. Expression of retinoic acid receptor β (RARβ), hepatocyte growth factor (HGF), cellular retinoic acid-binding protein II (CRABPII), vimentin, E-cadherin, Snail, and β-catenin was assessed by immunoblotting. The cellular localization of vimentin and β-catenin was determined by immunocytochemistry. Changes in cell morphology were assessed by phase contrast microscopy. Gene expression profiling demonstrated differential expression of 953 and 1458 genes after C-peptide exposure for 18 h or 48 h, respectively. From these, members of the antifibrotic retinoic acid (RA)- and HGF-signaling pathways were selected. Immunoblotting demonstrated that C-peptide increased RARβ, CRABPII, and HGF. We confirmed a role for RA in reversal of TGF-β1-induced changes associated with epithelial-mesenchymal transition, including expression changes in Snail, E-cadherin, vimetin, and redistribution of β-catenin. Importantly, these TGF-β1-induced changes were inhibited by C-peptide. Further, effects of TGF-β1 on Snail and E-cadherin expression were blocked by HGF, and inhibitory effects of C-peptide were removed by blockade of HGF activity. This study identifies a novel role for HGF as an effector of C-peptide, possibly via an RA-signaling pathway, highlighting C-peptide as a potential therapy for diabetic nephropathy.

C-peptide induces transcription of multiple genes in proximal tubular cells, protecting against TGFβ mediated injury by upregulation of retinoic acid and HGF signaling pathways.

Additional Information:Accepted: January 21, 2010 Published Online: July 02, 2013
Keywords:Molecular endocrinology
Subjects:C Biological Sciences > C720 Biological Chemistry
Divisions:College of Science > School of Life Sciences
ID Code:14153
Deposited On:28 May 2014 14:57

Repository Staff Only: item control page