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

INSERM U.489, Hôpital Tenon, Paris 75020

Ying Lu

INSERM U.489, Hôpital Tenon, Paris 75020

Jean-Claude Dussaule

AP-HP, Laboratoire de Physiologie, UFR St Antoine, Paris 75012, France

Christos Chatziantoniou

INSERM U.489, Hôpital Tenon, Paris 75020, christos. chatziantniou@tnn. ap-hop-paris.fr

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 N^Gnitro-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 ET_A/B antagonist), co-treatment with both agents, or vehicle for an additional period of four weeks. Blockade of AT₁and/or ET_A/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.

Key Words: hypertension • nephroangiosclerosis • regression of fibrosis • extracellular matrix

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Journal of Renin-Angiotensin-Aldosterone System, Vol. 2, No. 1 suppl, S211-S216 (2001)
DOI: 10.1177/14703203010020013701


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This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Boffa, J.-J. Articles by Chatziantoniou, C. Search for Related Content PubMed Articles by Boffa, J.-J. Articles by Chatziantoniou, C. Social Bookmarking                         What's this?