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Proinsulin C-Peptide Antagonizes the Profibrotic Effects of TGF-β1 via Up-Regulation of Retinoic Acid and HGF-Related Signaling Pathways

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posted on 2010-06-08, 15:34 authored by Claire E. Hills, Gary B. Willars, Nigel J. Brunskill
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.

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Citation

Molecular Endocrinology, 2010, 24 (4), pp. 822-831.

Alternative title

Microarray analysis reveals up-regulation of retinoic acid and hepatocyte growth factor related signaling pathways by pro-insulin C-peptide in kidney proximal tubular cells: Antagonism of the pro-fibrotic effects of TGF-β1

Published in

Molecular Endocrinology

Publisher

Endocrine Society

issn

0888-8809

Copyright date

2010

Available date

2010-06-08

Publisher version

http://press.endocrine.org/doi/abs/10.1210/me.2009-0391

Language

en

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