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Epidermal growth factor receptor inhibitor PKI-166 governs cardiovascular protection without beneficial effects on the kidney in hypertensive 5/6 nephrectomized rats

Ula, N and Mulder, G.M and Vavrinec, P and Landheer, S.W. and Gurdal, H and Goris, Maaike and van Dokkum, R.P.E. and Buikema, H and van Goor, H and Henning, R.H. (2013) Epidermal growth factor receptor inhibitor PKI-166 governs cardiovascular protection without beneficial effects on the kidney in hypertensive 5/6 nephrectomized rats. J Pharmacol Exp Ther, 345 (3). pp. 393-403. ISSN 1521-0103

Abstract

Background--Transactivation of epidermal growth factor receptor (EGFR) signaling by G-protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, cardiac and vascular hypertrophy. As the therapeutic potential of EGFR inhibition in these conditions is currently unknown, we studied renal, cardiac and vascular effects of the EGFR kinase inhibitor PKI-166 in the hypertensive chronic kidney disease (CKD) model.
Methods and Results--Rats underwent 5/6 nephrectomy (5/6Nx) and were treated with PKI-166 (50 mg/kg/day), lisinopril (5 mg/kg/day) or vehicle from week 6 after disease induction until week 12. Sham operated animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx including proteinuria, decreased creatinine clearance and higher glomerulosclerosis, whereas these were attenuated by lisinopril. Despite the absence of effects on renal damage, PKI-166 treatment attenuated the progression of hypertension and maintained cardiac function (LVEDP) to a similar extent as lisinopril. Moreover, the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II in vehicle-treated 5/6Nx rats was restored by both PKI and lisinopril treatment. Small mesenteric arteries of vehicle-treated 5/6Nx rats failed to develop myogenic tone, which was completely restored by PKI and lisinopril treatment.
Conclusions-- Blockade of the EGFR pathway displays a therapeutic CV benefit which was independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.

Item Type: Article
Additional Information: previous disclosurers - Abstract at American Society of nephrology 2010, Oak No. 3226
Keywords: Cardiovascular diseases
Date Deposited: 04 May 2016 23:45
Last Modified: 04 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/3696

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