Hills, Claire E., Willars, G. B. and Brunskill, N. J.. (2010) Proinsulin C-Peptide Antagonizes the Profibrotic Effects of TGF- 1 via Up-Regulation of Retinoic Acid and HGF-Related Signaling Pathways. Molecular Endocrinology, Vol.24 (No.4). pp. 822-831. ISSN 0888-8809

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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-beta 1 in a human proximal tubular cell line, HK-2. Expression of retinoic acid receptor beta (RAR beta), hepatocyte growth factor (HGF), cellular retinoic acid-binding protein II (CRABPII), vimentin, E-cadherin, Snail, and beta-catenin was assessed by immunoblotting. The cellular localization of vimentin and beta-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 RAR beta, CRABPII, and HGF. We confirmed a role for RA in reversal of TGF-beta 1-induced changes associated with epithelial-mesenchymal transition, including expression changes in Snail, E-cadherin, vimetin, and redistribution of beta-catenin. Importantly, these TGF-beta 1-induced changes were inhibited by C-peptide. Further, effects of TGF-beta 1 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

Item Type:	Journal Article
Subjects:	Q Science > Q Science (General)
Divisions:	Faculty of Science > Life Sciences (2010- )
Journal or Publication Title:	Molecular Endocrinology
Publisher:	The Endocrine Society
ISSN:	0888-8809
Date:	2010
Volume:	Vol.24
Number:	No.4
Number of Pages:	10
Page Range:	pp. 822-831
Identification Number:	10.1210/me.2009-0391
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Medical Research Council (MRC) UK
Grant number:	G0500688
URI:	http://wrap.warwick.ac.uk/id/eprint/42634

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