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Article Dans Une Revue PLoS ONE Année : 2015

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

Résumé

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 [i]in vitro[/i] using bioluminescence resonance energy transfer in HEK293 cells and [i]in vivo[/i] 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 [i]in vivo[/i] 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.

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Autre [q-bio.OT]
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hal-01353265 , version 1 (10-08-2016)

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Mohammed Akli Ayoub, Yuan Zhang, Robyn S. Kelly, Heng B. See, Elizabeth K.M. Johnstone, et al.. Functional interaction between angiotensin II receptor type 1 and chemokine (C-C Motif) receptor 2 with implications for chronic kidney disease. PLoS ONE, 2015, 10 (3), pp.1-22. ⟨10.1371/journal.pone.0119803⟩. ⟨hal-01353265⟩
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