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PPAR Research
Volume 2013, Article ID 982462, 8 pages
Research Article

Combined Effects of PPARγ Agonists and Epidermal Growth Factor Receptor Inhibitors in Human Proximal Tubule Cells

Department of Medicine, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney, Australia

Received 3 December 2012; Accepted 25 January 2013

Academic Editor: Tom Hsun-Wei Huang

Copyright © 2013 Katherine Pegg et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


We aimed to determine whether epidermal growth factor receptor (EGFR) inhibition, in addition to a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, prevents high-glucose-induced proximal tubular fibrosis, inflammation, and sodium and water retention in human proximal tubule cells exposed to normal glucose; high glucose; high glucose with the PPARγ agonist pioglitazone or with the P-EGFR inhibitor, gefitinib; or high glucose with both pioglitazone and gefitinib. We have shown that high glucose increases AP-1 and NFκB binding activity, downstream phosphorylation of EGFR and Erk1/2, and fibronectin and collagen IV expression. Pioglitazone reversed these effects but upregulated NHE3 and AQP1 expression. Gefitinib inhibited high glucose induced fibronectin and collagen IV, and EGFR and Erk1/2 phosphorylation and reversed pioglitazone-induced increases in NHE3 and AQP1 expression. Our data suggests that combination of an EGFR inhibitor and a PPARγ agonist mitigates high-glucose-induced fibrosis and inflammation and reverses the upregulation of transporters and channels involved in sodium and water retention in human proximal tubule cells. Hence EGFR blockade may hold promise, not only in limiting tubulointerstitial pathology in diabetic nephropathy, but also in limiting the sodium and water retention observed in patients with diabetes and exacerbated by PPARγ agonists.