Abstract
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, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol (PKI-166) in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham 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, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.
Footnotes
- Received January 20, 2013.
- Accepted March 21, 2013.
N.U. and G.M.M. contributed equally to this work.
This study was supported by research grants from the Dutch Kidney Foundation [2006.2166]; and The Scientific and Technological Research Council of Turkey (SBAG-109S125).
Part of this study has been presented as a poster at the following meeting: Vavrinec P, Mulder GM, Van Dokkum RP, Buikema H, Landheer S, Goris M, van Goor H, Gurdal H, Henning RH, and Ulu N (2010) Epidermal growth factor receptor inhibitor PKI-166 governs cardiovascular protection without renal protection in 5/6 nephrectomized rats. American Society of Nephrology Renal Week; 2010 Nov 16–21; Denver, CO.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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