title: β-arrestin-1 drives endothelin-1-mediated podocyte activation and sustains renal injury.
abstract: Activation of endothelin-A receptor (ET(A)R) 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(A)R activation and increased β-arrestin-1 expression. Activated ET(A)R 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 ET(A)R-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 ET(A)R 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 ET(A)R antagonism for a group of diseases still needing a specific treatment.
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Bergamo, Italy;
authors.forename: Simona
authors.initials: S
authors.lastname: Buelli
authors.forename: Laura
authors.initials: L
authors.lastname: Rosanò
authors.forename: Elena
authors.initials: E
authors.lastname: Gagliardini
authors.forename: Daniela
authors.initials: D
authors.lastname: Corna
authors.forename: Lorena
authors.initials: L
authors.lastname: Longaretti
authors.forename: Anna
authors.initials: A
authors.lastname: Pezzotta
authors.forename: Luca
authors.initials: L
authors.lastname: Perico
authors.forename: Sara
authors.initials: S
authors.lastname: Conti
authors.forename: Paola
authors.initials: P
authors.lastname: Rizzo
authors.forename: Rubina
authors.initials: R
authors.lastname: Novelli
authors.forename: Marina
authors.initials: M
authors.lastname: Morigi
authors.forename: Carlamaria
authors.initials: C
authors.lastname: Zoja
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Anna
authors.initials: A
authors.lastname: Bagnato
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
mesh_terms: D000818:Animals; D019390:Arrestins / Q000502:physiology*; D002465:Cell Movement; D004195:Disease Models, Animal; D004317:Doxorubicin; D019332:Endothelin-1 / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D050199:Podocytes / Q000502:physiology*; D044022:Receptor, Endothelin A / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D051176:beta Catenin / Q000378:metabolism; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C000605253:ARRB1 protein, human; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D004317:Doxorubicin; D066246:ErbB Receptors; D019061:src-Family Kinases