Tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) is driven by
increased levels of angiotensin II (Ang II). In this study, we examined the time course
of the fibrotic process in rats with UUO and explored the effect of delayed administration
of an angiotensin converting enzyme (ACE) inhibitor, enalapril, on the tubulo-interstitial
fibrosis of obstructive uropathy. Rats were sacrificed at 3, 5, 8, or 10 days after
UUO was initiated. Some rats did not receive treatment, whereas others were treated
with enalapril from day 4 to day 8 or from day 6 to day 10 after the onset of UUO.
The levels of mRNA for transforming growth factor beta 1 (TGF-beta 1), collagen type
IV (collagen IV), and tissue inhibitor of metalloproteinase (TIMP-1) were measured
at each time point by reverse transcription-polymerase chain reaction (RT-PCR). The
relative volume of the tubulointerstitium (Vv) was measured by a point-counting method.
Monocyte/macrophage infiltration and collagen IV protein deposition were examined
histologically using specific antibodies. There were significant increases in TGF-beta
1, TIMP-1, and collagen IV mRNAs in the obstructed kidney. Treatment with enalapril
on day 4 through day 8 or on day 6 through day 10 significantly reduced the elevated
mRNA levels of these compounds in the obstructed kidney. Histological studies showed
augmented Vv, monocyte/macrophage infiltration, interstitial alpha-smooth muscle actin
expression, and collagen IV protein deposition on days 3, 5, 8, or 10 of UUO; enalapril
treatment from day 4 to 8 or from day 6 to 10 halted and to an extent reversed these
increases. These data suggest that enalapril administration after several days of
UUO is an effective means of preventing the progression of tubulointerstitial fibrosis
of obstructive uropathy.