Unilateral
ureteral obstruction (UUO) is a well-established model for the study of interstitial
fibrosis in the kidney. It has been shown that the renin-angiotensin system plays a central role in the progression of interstitial
fibrosis. Recent studies indicate that
endothelin, a powerful vasoconstrictive
peptide, may play an important role in some types of renal disease. To investigate the effects of
angiotensin II on
endothelin and its receptors in the kidney, mice were subjected to UUO and treated with or without
enalapril, an orally active
angiotensin-converting enzyme inhibitor, in their
drinking water (100 mg/l). The animals were killed 5 days later. Using RT coupled with PCR, we measured the levels of
endothelin-1,
endothelin A, and
endothelin B (ET(B)) along with
transforming growth factor-beta,
TNF-alpha, and
collagen type IV mRNA expression in the kidney with UUO and the contralateral kidney along with interstitial expansion in the kidney cortex by a standard point counting method. We found that
enalapril administration ameliorated the increased expression of ET-1
mRNA in the obstructed kidney by 44% (P < 0.02). Although the level of
endothelin A
mRNA expression was significantly increased in the obstructed kidney, it was not affected by
enalapril. We found that
enalapril treatment increased ET(B)
mRNA expression by 115% (P < 0.05) and
protein expression (measured by Western blot) in the kidney with an obstructed ureter.
Enalapril treatment alone inhibited the expansion of interstitial volume due to UUO by 52%. Cotreatment with
enalapril and the ET(B) receptor antagonist
BQ-788 inhibited the expression of interstitial volume by only 19%. This study confirms that
enalapril inhibits the interstitial
fibrosis in UUO kidneys. It also suggests a beneficial and unforeseen effect of
enalapril on the obstructed kidney by potentially stimulating the production of
nitric oxide through an increased expression of the ET(B) receptor.