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Abstract
Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the
obstructed kidney (OBK). In this study we report that a specific angiotensin II (Ang
II) receptor antagonists, SC-51316, ameliorates the expansion of the renal cortical
interstitium in the OBK of the rat at five days of UUO. This is similar to the effect
of an angiotensin converting enzyme (ACE) inhibitor, enalapril. SC-51316 (20 mg/liter
in the drinking water) or enalapril (200 mg/liter in the drinking water) was administered
beginning 24 hours before UUO and continued through five days after UUO. The relative
volume of the tubulointerstitium (Vv) was measured by a point-counting method, and
monocyte/macrophage infiltration, alpha smooth muscle actin (alpha SMA), proliferating
cell nuclear antigen (PCNA), and collagen type IV (collagen IV) protein deposition
were examined histologically using specific antibodies. We also examined the mRNA
levels of transforming growth factor beta 1 (TGF-beta 1) and collagen IV by reverse
transcription polymerase chain reaction. In untreated rats with UUO, Vv was remarkably
expanded; collagen IV and alpha SMA protein deposition in the interstitium and PCNA
labeling of nuclei were increased. These changes were significantly ameliorated by
administration of an ACE inhibitor or an Ang II receptor antagonist. A monocyte/macrophage
infiltration was evident in the OBK of untreated or Ang II receptor antagonist treated
rats but was greatly reduced in the OBK of rats given enalapril. Increased expression
of TGF-beta 1 mRNA and collagen IV mRNA was blunted (40 to 75%) by the administration
of Ang II receptor antagonist or enalapril. The Ang II receptor antagonist or the
ACE inhibitor did not affect the contralateral kidney of rats with UUO or the control
kidney of normal rats. This study indicates that the renin-angiotensin system has
a major role in the pathogenesis of the tubulointerstitial fibrosis of obstructive
nephropathy. The tubulointerstitial fibrosis of obstructive nephropathy is most likely
mediated by an increased level of Ang II in renal tissue.