Angiotensin II upregulates tumor necrosis factor-α (TNF-α) 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-α 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-α 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-α mRNA and transforming growth factor-β1 (TGF-β1) 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-α and TGF-β1 mRNA and their proteins to near normal levels. Also, α-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-α 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.
Angiotensin II‐induced natriuresis is attenuated in knockout mice lacking the receptors for tumor necrosis factor‐α
