Hills, Claire E., Al-Rasheed, N., Al-Rasheed, N., Willars, G. B. and Brunskill, N. J.. (2008) C-peptide reverses TGF- 1-induced changes in renal proximal tubular cells: implications for treatment of diabetic nephropathy. AJP: Renal Physiology, Vol.296 (No.3). F614-F621. ISSN 0363-6127

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Abstract

Hills CE, Al-Rasheed N, Al-Rasheed N, Willars GB, Brunskill NJ. C-peptide reverses TGF-beta 1-induced changes in renal proximal tubular cells: implications for treatment of diabetic nephropathy. Am J Physiol Renal Physiol 296: F614-F621, 2009. First published December 17, 2008; doi:10.1152/ajprenal.90500.2008.-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-beta 1 (TGF-beta 1) 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-beta 1 signaling pathways and thus block development of EMT in HK2 human kidney proximal tubular cells. Cells were incubated with TGF-beta 1 either alone or with C-peptide in low or high glucose. Changes in cell morphology, TGF-beta 1 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-beta 1-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-beta 1-induced upregulation of expression of both type I and type II TGF-beta 1 receptors and attenuated TGF-beta 1-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-beta 1 and suggest a role or c-peptide as a renoprotective agent in diabetic nephropathy.

Item Type:	Journal Article
Subjects:	Q Science > Q Science (General)
Divisions:	Faculty of Science > Life Sciences (2010- )
Journal or Publication Title:	AJP: Renal Physiology
Publisher:	American Physiological Society
ISSN:	0363-6127
Official Date:	2008
Volume:	Vol.296
Number:	No.3
Number of Pages:	8
Page Range:	F614-F621
Identification Number:	10.1152/ajprenal.90500.2008
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Medical Research Council of Great Britain
URI:	http://wrap.warwick.ac.uk/id/eprint/42628

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