Functional interaction between angiotensin ii receptor type 1 and chemokine (C-C motif) receptor 2 with implications for chronic kidney disease

Mohammed Akli Ayoub, Yuan Zhang, Robyn S. Kelly, Heng B. See, Elizabeth K.M. Johnstone, Elizabeth A. McCall, James H. Williams, Darren J. Kelly, Kevin D.G. Pfleger

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Understanding functional interactions between G protein-coupled receptors is of great physiological and pathophysiological importance. Heteromerization provides one important potential mechanism for such interaction between different signalling pathways via macromolecular complex formation. Previous studies suggested a functional interplay between angiotensin II receptor type 1 (AT1) and Chemokine (C-C motif) Receptor 2 (CCR2). However the molecular mechanisms are not understood.We investigated AT1-CCR2 functional interaction in vitro using bioluminescence resonance energy transfer in HEK293 cells and in vivo using subtotal-nephrectomized rats as a well-established model for chronic kidney disease. Our data revealed functional heteromers of these receptors resulting in CCR2-Gαi1 coupling being sensitive to AT1 activation, as well as apparent enhanced β-arrestin2 recruitment with agonist co-stimulation that is synergistically reversed by combined antagonist treatment. Moreover, we present in vivo findings where combined treatment with AT1- and CCR2-selective inhibitors was synergistically beneficial in terms of decreasing proteinuria, reducing podocyte loss and preventing renal injury independent of blood pressure in the subtotal-nephrectomized rat model. Our findings further support a role for G protein-coupled receptor functional heteromerization in pathophysiology and provide insights into previous observations indicating the importance of AT1-CCR2 functional interaction in inflammation, renal and hypertensive disorders.

Original languageEnglish
Article numbere0119803
JournalPLoS ONE
Volume10
Issue number3
DOIs
Publication statusPublished - Mar 25 2015
Externally publishedYes

ASJC Scopus subject areas

  • General

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