Endothelin Antagonism Inhibits Collagen I Gene Activation and Leads to the Regression of Renal Vascular Fibrosis During Hypertension
In previous studies (J.Clin.Invest. 101: 2781, 1998) we have observed that endothelin participates in the development of nephroangio- and glomerulo-sclerosis during hypertension. The present study has investigated whether endothelin antagonism leads to the regression of renal sclerotic lesions observed in late phases of hypertension. Experiments were performed in transgenic mice harboring the luciferase reporter gene under the control of the collagen I-α2 chain promoter. Hypertension was induced by inhibiting endogenous NO synthesis (L-NAME) for a 30-wk period. Systolic pressure gradually increased folIowing L-NAME administration, reaching a plateau of 165 mmHg after 10 wk of treatment. At the same time, collagen I gene expression was increased four-and ten-fold compared to control in afferent arterioles and glomeruli, respectively (p<0.01). This increase was accompanied by abnormal accumulation of collagens within the renal vasculature, as evidenced by Sirius red staining. When renal vascular lesions were established (20 wk of L-NAME treatment), bosentan, a mixed endothelin antagonist, was administered in a subgroup of animals for an additional period of 10 wk. Bosentan co-administration did not alter the increased systolic pressure at 30 wk (167±4 vs. 165±5 mmHg for the L-NAME and L-NAME+bosentan groups, respectively); in contrast, collagen I gene activity returned to control levels in renal vessels and glomeruli during endothelin receptor antagonism. This effect of bosentan was accompanied by a net improvement of renal vascular morphology as collagen and extracellular matrix deposition were substentially reduced in this group of animals (p<0.01 vs. L-NAME 20 and/or 30 wk). These data indicate that endothelin participates in the mechanisms maintaining renal vascular fibrosis by activating collagen I gene. Antagonism of endothelin normalizes collagen synthesis and regresses renal vascular fibrosis without altering systemic hemodynamics, suggesting thus, that endothelin receptor antagonists can provide a complementary approach to treat renal fibrotic complications associated to hypertension.