β-Arrestin-1 Drives Endothelin-1-Mediated Podocyte Activation and Sustains Renal Injury

• Published in: Journal of the American Society of Nephrology 2014-03, Vol.25 (3), p.523-533
• Main Authors: BUELLI, Simona, ROSANO, Laura, MORIGI, Marina, ZOJA, Carlamaria, REMUZZI, Giuseppe, BAGNATO, Anna, BENIGNI, Ariela, GAGLIARDINI, Elena, CORNA, Daniela, LONGARETTI, Lorena, PEZZOTTA, Anna, PERICO, Luca, CONTI, Sara, RIZZO, Paola, NOVELLI, Rubina
• Format: Article
• Language: English
• Subjects: Animals; Arrestins - physiology; Basic Research; beta Catenin - metabolism; beta-Arrestin 1; beta-Arrestins; Biological and medical sciences; Cell Movement; Disease Models, Animal; Doxorubicin; Endothelin-1 - metabolism; Female; Glomerulonephritis - chemically induced; Glomerulonephritis - metabolism; Humans; Injuries of the urinary system. Foreign bodies. Diseases due to physical agents; Kidneys; Male; Medical sciences; Mice; Mice, Inbred BALB C; Middle Aged; Nephrology. Urinary tract diseases; Podocytes - physiology; Receptor, Endothelin A - metabolism; Receptor, Epidermal Growth Factor - metabolism; Snail Family Transcription Factors; src-Family Kinases - metabolism; Transcription Factors - metabolism; Transcriptional Activation; Traumas. Diseases due to physical agents; Urinary system involvement in other diseases. Miscellaneous
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2013040362

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.