Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive nephropathy.
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.
Ishidoya
S
S
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Morrissey
J
J
McCracken
R
R
Klahr
S
S
D000199:Actins / Q000032:analysis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D003094:Collagen / Q000032:analysis / Q000235:genetics; D004656:Enalapril / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D006023:Glycoproteins / Q000235:genetics; D007150:Immunohistochemistry; D008264:Macrophages / Q000473:pathology; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000737:chemistry; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D011480:Protease Inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta / Q000235:genetics; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D006023:Glycoproteins; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D004656:Enalapril; D003094:Collagen