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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/F614    most recent 90500.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hills, C. E. Articles by Brunskill, N. J. Search for Related Content PubMed PubMed Citation Articles by Hills, C. E. Articles by Brunskill, N. J.

C-peptide reverses TGF-β1-induced changes in renal proximal tubular cells: implications for treatment of diabetic nephropathy

¹Department of Infection, Immunity and Inflammation, University of Leicester School of Medicine, Leicester; ²Department of Pharmacology, King Saud University, Riyadh, Saudi Arabia; and ³Department of Cell Physiology and Pharmacology, University of Leicester School of Medicine, and ⁴Department of Nephrology, Leicester General Hospital, Leicester, United Kingdom

Submitted 19 August 2008 ; accepted in final form 12 December 2008

The crucial pathology underlying progressive chronic kidney disease in diabetes is tubulointerstitial fibrosis. Central to this process is epithelial-mesenchymal transformation (EMT) of proximal tubular epithelial cells driven by maladaptive transforming growth factor-β1 (TGF-β1) signaling. Novel signaling roles for C-peptide have recently been discovered with evidence emerging that C-peptide may mitigate microvascular complications of diabetes. We studied the potential for C-peptide to interrupt injurious TGF-β1 signaling pathways and thus block development of EMT in HK2 human kidney proximal tubular cells. Cells were incubated with TGF-β1 either alone or with C-peptide in low or high glucose. Changes in cell morphology, TGF-β1 receptor expression, vimentin, E-cadherin, and phosphorylated Smads were assessed. Luciferase reporters were used to assess Smad activity. The cytoskeleton was visualized by TRITC-phalloidin staining. The typical TGF-β1-stimulated, EMT-associated morphological alterations of proximal tubular cells, including increased vimentin expression, decreased E-cadherin expression, and cytoskeletal rearrangements, were prevented by C-peptide treatment. C-peptide also blocked TGF-β1-induced upregulation of expression of both type I and type II TGF-β1 receptors and attenuated TGF-β1-mediated Smad phosphorylation and Smad transcriptional activity. These effects of C-peptide were inhibited by pertussis toxin. The results demonstrate that C-peptide almost completely reversed the morphological changes in PT cells induced by TGF-β1 and suggest a role or C-peptide as a renoprotective agent in diabetic nephropathy.

tubulointerstitial fibrosis