Mechanisms mediating the renal profibrotic actions of vasoactive peptides in transgenic mice.
Transgenic mice are useful tools to investigate the mechanisms of the renal profibrotic actions of endothelin and angiotensin II. The overexpression of angiotensinogen and renin genes induces renal sclerosis independently of changes in systemic hemodynamics. The same results are observed when the endothelin-1 gene is overexpressed. Transgenic mice harboring the luciferase gene, under the control of the collagen I alpha2 chain promoter, and made hypertensive by induction of a nitric oxide (NO) deficiency have been studied. In this strain of mice, luciferase activity is an early index of renal and vascular fibrosis. Luciferase activity was increased in preglomerular arterioles and glomeruli when mice were treated with N:(omega)-nitro-L-arginine methyl ester, an inhibitor of NO synthases. Bosentan (an endothelin receptor antagonist) was as efficient as losartan (an AT1 receptor antagonist) in preventing renal fibrosis, although it did not decrease BP. In short-term experiments, angiotensin II produced an increase in luciferase activity that was entirely prevented by losartan but also by bosentan. It can be concluded that, during chronic inhibition of NO, the collagen I gene is activated, which contributes to the development of nephroangiosclerosis and glomerulosclerosis. Angiotensin II plays a major role in this fibrogenic process, and its effect is at least partly independent of systemic hemodynamics and mediated by the profibrotic action of endothelin-1.
Dussaule
J C
JC
Department of Physiology, UFR Saint-Antoine AP-HP, Paris, France. jeanclaude@sat.ap-hop-paris.fr
Tharaux
P L
PL
Boffa
J J
JJ
Fakhouri
F
F
Ardaillou
R
R
Chatziantoniou
C
C
D000818:Animals; D016232:Endothelins / Q000235:genetics / Q000502:physiology*; D005355:Fibrosis / Q000209:etiology; D015870:Gene Expression; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*
D016232:Endothelins