ET1 and Renal and Cardiac Target Organ Damage in Experimental Hypertension

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ET-1 plays a role in renal and cardiac target organ damage in hypertension. ET-1 production is enhanced under conditions of salt loading, and via renal ETB receptor activation, inhibits sodium re-absorption (46). Ang II infusion combined with high salt increases renal ET-1 (47). In Ang Il-infused mice, the dual ETa/ETb receptor blocker bosentan partially prevented the activation of the procollagen gene (48). However, Rothermund et al. studied transgenic rats overexpressing the ren2 gene (TGR(mRen2)27) that have renin-dependent hypertension (Ren2) and were treated between 10 and 30 wk of age with the selective ETa receptor antagonist darusentan or the ETa/ETb receptor antagonist LU420627 (49). The elevated blood pressure and mortality of Ren2 was not affected by either ET receptor antagonist. Proteinuria and glomerulosclerosis, tubulo-interstitial damage, and renal osteopontin mRNA expression were reduced by an angiotensin receptor blocker but were unchanged in ET receptor blocker-treated Ren2-rats, indicating that ET-1 is not involved in the renal damage and mortality in primary renin-dependent hypertension. On the other hand, in salt-loaded SHR-SP, increases in renal ET-1 were associated with increases in transforming growth factor (TGF)-^l, basic fibroblast growth factor (bFGF), procollagen I expression and matrix metallo-proteinase (MMP)-2 activity, which in turn were normalized by a selective ETa antagonist. This indicates that ET-1 plays a role in renal fibrosis through growth factors and induction of inflammation (50).

In the heart, ETa blockade prevented enhanced TGF-^1 expression and collagen deposition in DOCA-salt rats (51). ETa receptors modulated the expression of inflammatory mediators such as NFkB and adhesion molecules, and the activation of the anti-apoptotic molecule X inhibitor of apoptosis peptide (xIAP) (52). Thus, regulation of the inflammatory process may affect mechanisms that play a role in cardiac remodeling such as apoptosis and cell hypertrophy. Inhibition of NFkB has indeed prevented anti-apoptotic and hypertrophic actions of ET-1 (53). NFkB is redox sensitive and is activated by NADPH oxidase-derived superoxide anion (54). ET-1-dependent cardiac hypertrophy is induced by the activation of NADPH oxidase and MAPK (55). Combined ETa/ETb prevented target organ damage in Ang II-infused rats through decreased activation of NFkB and downregulation of ICAM-1, vascular cellular adhesion molecule (VCAM)-1, and tissue factor, underlining the pro-inflammatory effects of ET-1 that occur partly interacting with the renin-angiotensin-aldosterone system (RAAS) (56). However, it should be noted that there is an evidence that ET-1 and the RAAS act in parallel rather than in series, as suggested by recent work (49,57,58). Indeed, in the TGR(mRen2)27, a primary form of renin-dependent hypertension, bosentan was ineffective in lowering blood pressure (56) as also reported with an ETa selective blocker in other studies (58). Among components of the RAAS, aldosterone may contribute to both cardiac and vascular damage mediated by ET-1, similarly to effects already described for the mineralocorticoid DOCA. Indeed, we recently showed that ETA antagonism prevents vascular remodeling and cardiac and vascular fibrosis in aldosterone-infused rats (31,59,60).

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