Improvements of renal lesions and function by angiotensin and endothelin receptor antagonism in nitric oxide-deficient rats

• Main Authors: Jean-Jacques Boffa, Ying Lu, Jean-Claude Dussaule, Christos Chatziantoniou
• Format: Article
• Language: English
• Published: Hindawi - SAGE Publishing 2001-03-01
• Series: Journal of the Renin-Angiotensin-Aldosterone System
• Online Access: https://doi.org/10.1177/14703203010020013701
• ISSN: 1470-3203; 1752-8976

In previous studies, we have observed that antagonism of angiotensin or endothelin receptors prevented the development of nephroangio- and glomerulo-sclerosis during hypertension by inhibiting collagen I gene synthesis, through a mechanism independent of systemic haemodynamics. The present study investigated whether treatment with angiotensin or endothelin receptor antagonists, given at doses that did not reduce blood pressure, could produce regression of renal sclerotic lesions and improve renal function during hypertension. Hypertension and renal vascular fibrosis were induced in rats by chronic inhibition of NO synthesis using NGnitro-L-arginine methyl ester (L-NAME). Systolic blood pressure gradually increased following L-NAME administration, reaching a plateau of 170 mmHg after four weeks of treatment. At the same time, urinary protein excretion and plasma creatinine concentration were increased ten- and three-fold compared with controls, respectively (p<0.001). This increase was accompanied by the appearance of sclerotic lesions within renal vessels and glomeruli, as evidenced by Masson's trichromic staining (sclerotic index 2.34±0.29 vs. 0.10±0.01 in L-NAME four weeks and control, respectively, p<0.001). Thereafter, the L-NAME treatment was combined with either losartan (an AT1receptor antagonist), bosentan (an ETA/B antagonist), co-treatment with both agents, or vehicle for an additional period of four weeks. Blockade of AT1and/or ETA/B-receptors significantly reduced urinary protein excretion and plasma creatinine levels (p<0.01) and substantially improved renal vascular histology (sclerotic index 1.78±0.13, 1.57±0.22 and 1.85±0.15 respectively, p<0.01, vs. L-NAME eight week) without altering the L-NAME-induced increase of systolic pressure. These data indicate that angiotensin II and endothelin-1 participate in the mechanism(s) of renal vascular fibrosis by increasing extracellular matrix formation. Treatment with their respective receptor antagonists leads to the regression of renal vascular fibrosis and to the improvement of renal function by a common antifibrogenic mechanism that is independent of systemic haemodynamics.