Activation of endothelin-A receptor (ETAR) by endothelin-1 (ET-1) drives epithelial-to-mesenchymal transition in ovarian tumor cells through β-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 α-smooth muscle actin. ET-1 promoted podocyte migration via ET AR activation and increased β-arrestin-1 expression. Activated ETAR recruited β-arrestin-1 to form a trimeric complex with Src leading to epithelial growth factor receptor (EGFR) transactivation and β-catenin phosphorylation, which promoted gene transcription of Snail. Increased Snail expression fostered ET-1-induced migration as confirmed by Snail knockdown experiments. Silencing of β-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; β-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 β-arrestin-1 and Snail. Increased β-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 © 2014 by the American Society of Nephrology.
|Titolo:||β-arrestin-1 drives endothelin-1-mediated podocyte activation and sustains renal injury|
|Parole Chiave:||Animals; Arrestins; Cell Movement; Disease Models, Animal; Doxorubicin; Endothelin-1; Female; Glomerulonephritis; Humans; Male; Mice; Mice, Inbred BALB C; Middle Aged; Podocytes; Receptor, Endothelin A; Receptor, Epidermal Growth Factor; Transcription Factors; Transcriptional Activation; beta Catenin; src-Family Kinases; Nephrology|
|Settore Scientifico Disciplinare:||Settore MED/14 - Nefrologia|
|Data di pubblicazione:||mar-2014|
|Digital Object Identifier (DOI):||10.1681/ASN.2013040362|
|Appare nelle tipologie:||01 - Articolo su periodico|