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Regression of renal vascular fibrosis by endothelin receptor antagonism
J J Boffa1, P L Tharaux, J C Dussaule
1INSERM U.489, Hôpital Tenon, Paris, France.
Abstract:
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.
Insights
Endothelin receptor antagonists reduced renal fibrosis in hypertensive mice by normalizing collagen I gene expression. This treatment improved survival and offered a new approach for hypertension-related kidney complications.
Area of Science:
- Nephrology
- Cardiovascular Research
- Molecular Biology
Background:
- Endothelin plays a role in hypertension-induced renal fibrosis by increasing collagen I gene synthesis.
- Renal vascular and glomerular fibrosis are significant complications of hypertension.
Purpose of the Study:
- To investigate if endothelin receptor antagonists can reverse established renal sclerotic lesions.
- To determine the effect of bosentan on collagen I gene expression and renal fibrosis in a mouse model of hypertension.
Main Methods:
- Hypertension was induced in transgenic mice using N(G)-nitro-L-arginine methyl ester (L-NAME).
- Collagen I gene expression was measured using a luciferase reporter system.
- Bosentan, an endothelin antagonist, was administered to a subgroup of hypertensive mice.
Main Results:
- L-NAME induced hypertension and increased collagen I gene expression in renal vessels and glomeruli.
- Bosentan treatment normalized collagen I gene activity despite sustained hypertension.
- Renal vascular lesions and mortality rates were significantly reduced in mice treated with bosentan.
Conclusions:
- Endothelin activation of collagen I gene synthesis contributes to renal vascular fibrosis in hypertension.
- Endothelin receptor antagonism promotes regression of renal fibrosis and improves survival.
- Endothelin antagonists represent a potential therapeutic strategy for hypertension-associated renal fibrotic complications.