Format

Send to

Choose Destination
PLoS One. 2015 Mar 25;10(3):e0119803. doi: 10.1371/journal.pone.0119803. eCollection 2015.

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

Author information

1
Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia; Centre for Medical Research, The University of Western Australia, Crawley, Western Australia, Australia.
2
Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
3
Dimerix Bioscience Limited, Nedlands, Western Australia, Australia.
4
Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia; Centre for Medical Research, The University of Western Australia, Crawley, Western Australia, Australia; Dimerix Bioscience Limited, Nedlands, Western Australia, Australia.

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.

PMID:
25807547
PMCID:
PMC4373786
DOI:
10.1371/journal.pone.0119803
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center