β-arrestin-1 drives endothelin-1-mediated podocyte activation and sustains renal injury

Activation of endothelin-A receptor (ETAR) by endothelin-1 (ET-1) drives epithelial-to-mesenchymal transition in ovarian tumor cells through \u3b2-arrestin signaling. Here, we investigated whether this pathogenetic pathway could affect podocyte phenotype in proliferative glomerular disorders. In cultured mouse podocytes, ET-1 caused loss of the podocyte differentiation marker synaptopodin and acquisition of the mesenchymal marker \u3b1-smooth muscle actin. ET-1 promoted podocyte migration via ET AR activation and increased \u3b2-arrestin-1 expression. Activated ETAR recruited \u3b2-arrestin-1 to form a trimeric complex with Src leading to epithelial growth factor receptor (EGFR) transactivation and \u3b2-catenin phosphorylation, which promoted gene transcription of Snail. Increased Snail expression fostered ET-1-induced migration as confirmed by Snail knockdown experiments. Silencing of \u3b2-arrestin-1 prevented podocyte phenotypic changes and motility and inhibited ETAR-driven signaling. In vitro findings were confirmed in doxorubicin (Adriamycin)-induced nephropathy. Mice receiving Adriamycin developed renal injury with loss of podocytes and hyperplastic lesion formation; \u3b2-arrestin-1 expression increased in visceral podocytes and in podocytes entrapped in pseudo-crescents. Administration of the selective ETAR antagonist sitaxsentan prevented podocyte loss, formation of the hyperplastic lesions, and normalized expression of glomerular \u3b2-arrestin-1 and Snail. Increased \u3b2-arrestin-1 levels in podocytes retrieved from crescents of patients with proliferative glomerulopathies confirmed the translational relevance of these findings and suggest the therapeutic potential of ETAR antagonism for a group of diseases still needing a specific treatment. Copyright \ua9 2014 by the American Society of Nephrology