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Proinsulin C-Peptide Antagonizes the Profibrotic Effects of TGF- 1 via Up-Regulation of Retinoic Acid and HGF-Related Signaling Pathways
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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. doi:10.1210/me.2009-0391 ISSN 0888-8809.
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Official URL: http://dx.doi.org/10.1210/me.2009-0391
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 | ||||
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Subjects: | Q Science > Q Science (General) | ||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | Molecular Endocrinology | ||||
Publisher: | The Endocrine Society | ||||
ISSN: | 0888-8809 | ||||
Official Date: | 2010 | ||||
Dates: |
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Volume: | Vol.24 | ||||
Number: | No.4 | ||||
Number of Pages: | 10 | ||||
Page Range: | pp. 822-831 | ||||
DOI: | 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 |
Data sourced from Thomson Reuters' Web of Knowledge
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