Endothelin-1 drives epithelial-mesenchymal transition in hypertensive nephroangiosclerosis

Background--tubulointerstitial fibrosis,the final outcome of most kidney diseases,involves activation of epithelial mesenchymal transition (emt). endothelin-1 (et-1) activates emt in cancer cells,but it is not known whether it drives emt in the kidney. we therefore tested the hypothesis that tubulointerstitial fibrosis involves emt driven by et-1. methods and results--transgenic tg[mren2]27 (tgren2) rats developing fulminant angiotensin ii-dependent hypertension with prominent cardiovascular and renal damage were submitted to drug treatments targeted to et-1 and/or angiotensin ii receptor or left untreated (controls). expressional changes of e-cadherin and a-smooth muscle actin (asma) were examined as markers of renal emt. in human kidney hk-2 proximal tubular cells expressing the etb receptor subtype,the effects of et-1 with or without et-1 antagonists were also investigated. the occurrence of renal fibrosis was associated with emt in control tgren2 rats,as evidenced by decreased e-cadherin and increased asma expression. irbesartan and the mixed et-1 receptor antagonist bosentan prevented these changes in a blood pressure-independent fashion (p < 0.001 for both versus controls). in hk-2 cells et-1 blunted e-cadherin expression,increased asma expression (both p < 0.01),collagen synthesis,and metalloproteinase activity (p < 0.005,all versus untreated cells). all changes were prevented by the selective etb receptor antagonist bq-788. evidence for involvement of the rho-kinase signaling pathway and dephosphorylation of yes-associated protein in emt was also found. conclusions--in angiotensin ii-dependent hypertension,et-1 acting via etb receptors and the rho-kinase and yes-associated protein induces emt and thereby renal fibrosis.