Unknown,Transcriptomics,Genomics,Proteomics

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C-peptide regulates early transcription in rat proximal tubular cells

ABSTRACT: C-peptide exerts beneficial effects on glomerular hyperfiltration in type I diabetic patients. As C-peptide localizes to the nucleus, we investigated the transcriptional activities of C-peptide in proximal tubular cells isolated from diabetic rats. Two groups of proximal tubular cells isolated from type I diabetic rats: 1 treated with C-peptide, and 1 untreated. 2-3 replicates per group.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Emma Lindahl

PROVIDER: E-GEOD-24687 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells.

Lindahl Emma E Nordquist Lina L Müller Patrick P El Agha Eli E Friederich Malou M Dahlman-Wright Karin K Palm Fredrik F Jörnvall Hans H

Diabetes/metabolism research and reviews 20111001 7

<h4>Background</h4>Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether the genes with altered transcription include those related to protective mechanisms.<h4>Methods</h4>The effect ...[more]

PMID: 21618400

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Project description: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-b1 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 transforming growth factor beta 1 (TGF-β1) in a human proximal tubular cell line, HK-2. Expression of retinoic acid receptor β (RARβ), hepatcoyte growth factor (HGF), cellular retinoic acid binding protein II (CRABPII), vimentin, E-cadherin, Snail and β-catenin was assessed by immunoblotting. The cellular localisation 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 1,458 genes after C-peptide exposure for 18h or 48h respectively. From these, members of the anti-fibrotic 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 (EMT), 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.

Dataset Information

C-peptide regulates early transcription in rat proximal tubular cells

Publications

Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells.

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