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

By Claire E. Hills, Nawal M. Al-Rasheed, Nouf Al-Rasheed, Gary B. Willars and Nigel J. Brunskill

Abstract

This paper was published as American Journal of Physiology - Renal Physiology, 2009, 296 (3), pp. F614-F621. It is available from http://ajprenal.physiology.org/cgi/content/abstract/296/3/F614. Doi: 10.1152/ajprenal.90500.2008Metadata only entryThe 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

Publisher: American Physiological Society
Year: 2009
DOI identifier: 10.1152/ajprenal.90500.2008
OAI identifier: oai:lra.le.ac.uk:2381/7711
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