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

Nadir Ulu*, Gemma M. Mulder, Peter Vavrinec, Sjoerd W. Landheer, Basak Duman-Dalkilic, Hakan Gurdal, Maaike Goris, Marry Duin, Richard P. E. van Dokkum, Hendrik Buikema, Harry van Goor, Robert H. Henning

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)393-403
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume345
Issue number3
DOIs
Publication statusPublished - Jun-2013

Keywords

  • EXPERIMENTAL RENAL-FAILURE
  • ANGIOTENSIN-II
  • HEART-FAILURE
  • EGF-RECEPTOR
  • CARDIAC-HYPERTROPHY
  • MYOGENIC CONSTRICTION
  • DIABETIC-NEPHROPATHY
  • RESISTANCE VESSELS
  • EJECTION FRACTION
  • CELL HYPERTROPHY

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