(Circulation. 1999;100:1901-1908.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Angiotensin II Activates Collagen Type I Gene in the Renal Vasculature of Transgenic Mice During Inhibition of Nitric Oxide Synthesis
Evidence for an Endothelin-Mediated Mechanism
From INSERM U.489, Hôpital Tenon, and AP-HP, Laboratoire de Physiologie, Faculté de Médecine St Antoine (J.-C.D.), Paris, France.
Background—Hypertension is frequently associated with renal vascular fibrosis. The purpose of this study was to investigate whether angiotensin II (Ang II) is involved in this fibrogenic process.
Methods and Results—Experiments were performed on transgenic mice
harboring the luciferase gene under the control of the collagen
I-
2 chain promoter [procol2(I)].
Hypertension was induced by chronic inhibition of NO synthesis
(NG-nitro-L-arginine methyl
ester, L-NAME). Procol2(I) activity started to increase
in the renal vasculature after 4 weeks of L-NAME treatment
(P<0.01) and at 14 weeks reached 3- and 8-fold
increases over control in afferent arterioles and glomeruli,
respectively (P<0.001). Losartan, an
AT1 receptor antagonist, given
simultaneously with L-NAME prevented the increase of
procol2(I) levels and attenuated the development of
renal vascular fibrosis without normalizing systolic pressure
increase. Because we found previously that endothelin mediated renal
vascular fibrosis in the L-NAME model, the interaction between Ang II,
endothelin, and procol2(I) was investigated in ex vivo
and short-term in vivo experiments. In both conditions, the Ang
II–induced activation of procol2(I) in renal cortex was
blocked by an endothelin receptor antagonist.
Conclusions—During chronic inhibition of NO, the collagen I gene becomes activated, leading to the development of renal vascular fibrosis. Ang II is a major player in this fibrogenic process, and its effect on collagen I gene is independent of systemic hemodynamics and is at least partly mediated by the profibrogenic action of endothelin.
Key Words: hypertension • kidney • collagen • angiotensin • endothelin
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