Functional Interaction between Angiotensin II Receptor Type 1 and Chemokine (C-C motif) Receptor 2 with Implications for Chronic Kidney Disease

Mohammed Ayoub, Y. Zhang, R.S. Kelly, Ethan See, Elizabeth Johnstone, E.A. Mccall, J.H. Williams, D.J. Kelly, Kevin Pfleger

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Abstract

© 2015 Ayoub et al. 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
Number of pages22
JournalPLoS One
Volume10
Issue number3
DOIs
Publication statusPublished - 25 Mar 2015

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