Abstract P163: Endothelin-1 induces Epithelial-Mesenchymal Transition (EMT) in Human Renal Tubular Cells via Activation of RhoA /ROCK Kinase and Inhibition of YAP Pathways
We tested the hypothesis that tubulo-interstitial fibrosis (TIF), the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT) through angiotensin II- and endothelin-1 (ET-1)-mechanisms.
In a transgenic model of fulminant angiotensin II-dependent hypertension with early prominent renal damage, the TG(mRen2)27 rat (TGRen2), we found that the development of renal damage implied a decrease of the epithelial marker E-cadherin and an increase of the mesenchymal markers alpha SMA and vimentin, which indicated the occurrence of EMT. As treatment with the angiotensin II type 1 receptor antagonist irbesartan, or with the mixed ET-1 receptor antagonist bosentan, prevented these changes an involvement of both angiotensin II and ET-1 in EMT is suggested.
To confirm this contention we exposed HK-2 human kidney tubular cells to ET-1. This showed that ET-1 blunted the expression of E-cadherin, increased that of alpha SMA and vimentin, enhanced the synthesis of collagen, and also the activity of metalloproteinases (MMP). These changes implicated activation of Rho-kinase signaling pathway and de-phosphorylation of Yes-associated protein (YAP).
Hence, ex vivo and in vitro experiments demonstrated that EMT is a fundamental process in the TIF that accompanies the development of angiotensin II-dependent hypertension. Moreover, they suggested that EMT involves ET-1 acting via ETA and ETB receptors through activation of Rho-kinase and de-activation of YAP pathways.
Author Disclosures: T. Seccia: None. B. Caroccia: None. F. Gioco: None. M. Piazza: None. V. Buccella: None. B. Montini: None. D. Guidolin: None. E. Guerzoni: None. E. Pagnin: None. V. Ravarotto: None. L. Calò: None. A. Belloni: None. G. Rossi: None.
- © 2015 by American Heart Association, Inc.