Document Detail

Regression of renal vascular fibrosis by endothelin receptor antagonism.
MedLine Citation:
PMID:  11230324     Owner:  NLM     Status:  MEDLINE    
In previous studies, we have observed that endothelin participates in the progression of renal vascular and glomerular fibrosis during hypertension by activating collagen I gene synthesis. The present study investigated whether administration of endothelin receptor antagonists leads to the regression of renal sclerotic lesions. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter. Hypertension was induced by long-term inhibition of nitric oxide synthesis by N(G)-nitro-L-arginine methyl ester (L-NAME); systolic pressure gradually increased, reaching a plateau of 165 mm Hg after 10 weeks of hypertensive treatment. At the same time, collagen I gene expression was increased 2- and 5-fold compared with control animals in afferent arterioles and glomeruli, respectively (P<0.01). This increase was accompanied by the appearance of sclerotic lesions within the renal vasculature. When renal vascular lesions had been established (20 weeks of L-NAME), animals were divided into 2 subgroups: the one continued to receive L-NAME, whereas in the other, bosentan, a dual endothelin antagonist, was coadministered with L-NAME for an additional period of 10 weeks. Bosentan coadministration did not alter the increased systolic pressure at 30 weeks; in contrast, collagen I gene activity returned almost to control levels in renal vessels and glomeruli. In this subgroup of animals, renal vascular lesions (collagen and/or extracellular matrix deposition) and mortality rates were substantially reduced compared with untreated mice. These data indicate that endothelin participates in the mechanism(s) of renal vascular fibrosis by activating collagen I gene. Treatment with an endothelin antagonist normalizes expression of collagen I gene and leads to the regression of renal vascular fibrosis and to the improvement of survival, thus providing a complementary curative approach against renal fibrotic complications associated with hypertension.
J J Boffa; P L Tharaux; J C Dussaule; C Chatziantoniou
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Hypertension     Volume:  37     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2001 Feb 
Date Detail:
Created Date:  2001-03-20     Completed Date:  2001-04-26     Revised Date:  2013-06-18    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  490-6     Citation Subset:  IM    
INSERM U.489, Hôpital Tenon, Paris, France.
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MeSH Terms
Antihypertensive Agents / pharmacology
Blood Pressure
Collagen / biosynthesis,  genetics
Collagen Type I
Endothelins / antagonists & inhibitors*,  physiology
Gene Expression Regulation
Hypertension, Renovascular / chemically induced,  pathology,  prevention & control*
Kidney Glomerulus / pathology
Luciferases / genetics
Mice, Transgenic
NG-Nitroarginine Methyl Ester
Receptors, Endothelin / antagonists & inhibitors*
Renal Artery / metabolism,  pathology*
Staining and Labeling
Sulfonamides / administration & dosage,  pharmacology
Time Factors
Reg. No./Substance:
0/Antihypertensive Agents; 0/Collagen Type I; 0/Endothelins; 0/Receptors, Endothelin; 0/Sulfonamides; 0/alpha 2(I) collagen; 50903-99-6/NG-Nitroarginine Methyl Ester; 9007-34-5/Collagen; EC 1.13.12.-/Luciferases; Q326023R30/bosentan

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