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to the development of renal fibrosis
1 Departments of Internal Medicine, 2 Cell Biology and Physiology, and 3 Pathology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110-1092
Angiotensin II upregulates tumor
necrosis factor-
(TNF-) in the rat kidney with unilateral
ureteral obstruction (UUO). In a mouse model of UUO, we found that
tubulointerstitial fibrosis is blunted when the TNF- receptor,
TNFR1, is functionally knocked out. In this study, we used mutant mice
with UUO in which the angiotensin II receptor AT1a or the
TNF- receptors TNFR1 and TNFR2 were knocked out to elucidate
interactions between the two systems. The contribution of both systems
to renal fibrosis was assessed by treating TNFR1/TNFR2-double knockout
(KO) mice with an angiotensin-converting enzyme inhibitor, enalapril.
The increased interstitial volume (Vvint) in the C57BI/6
wild-type mouse was decreased in the AT1a KO from 32.8 ± 4.0 to 21.0 ± 3.7% (P < 0.005) or in the
TNFR1/TNFR2 KO to 22.3 ± 2.1% (P < 0.005). The Vvint of the TNFR1/TNFR2 KO was further
decreased to 15.2 ± 3.7% (P < 0.01) by
enalapril compared with no treatment. The induction of TNF- mRNA and
transforming growth factor-
1 (TGF-1) mRNA in the kidney with UUO
was significantly blunted in the AT1a or TNFR1/TNFR2 KO
mice compared with the wild-type mice. Treatment of the TNFR1/TNFR2 KO
mouse with enalapril reduced both TNF- and TGF-1 mRNA and their
proteins to near normal levels. Also, -smooth muscle actin
expression and myofibroblast proliferation were significantly inhibited
in the AT1a or TNFR1/TNFR2 KO mice, and they were further
inhibited in enalapril-treated TNFR1/TNFR2 KO mice. Incapacitating
the angiotensin II or the TNF- systems individually leads to partial
blunting of fibrosis. Incapacitating both systems, by using a
combination of genetic and pharmacological means, further inhibited
interstitial fibrosis and tubule atrophy in obstructive nephropathy.
interstitial volume; myofibroblast; tubulointerstitial fibrosis
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