Contributions of angiotensin II and tumor necrosis factor-α to the development of renal fibrosis

被引:128
|
作者
Guo, GJ
Morrissey, J
McCracken, R
Tolley, T
Liapis, H
Klahr, S
机构
[1] Washington Univ, Sch Med, Barnes Jewish Hosp, Dept Internal Med, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Barnes Jewish Hosp, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Barnes Jewish Hosp, Dept Pathol, St Louis, MO 63110 USA
关键词
interstitial volume; myofibroblast; tubulointerstitial fibrosis;
D O I
10.1152/ajprenal.2001.280.5.F777
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Angiotensin II upregulates tumor necrosis factor-alpha (TNF-alpha) 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-alpha receptor, TNFR1, is functionally knocked out. In this study, we used mutant mice with UUO in which the angiotensin II receptor AT(1a) or the TNF-alpha 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 (V(vint)) 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-<alpha> mRNA and transforming growth factor-beta1 (TGF-beta1) mRNA in the kidney with UUO was significantly blunted in the AT(1a) or TNFR1/TNFR2 KO mice compared with the wild-type mice. Treatment of the TNFR1/TNFR2 KO mouse with enalapril reduced both TNF-alpha and TGF-beta1 mRNA and their proteins to near normal levels. Also, alpha -smooth muscle actin expression and myofibroblast proliferation were significantly inhibited in the AT(1a) or TNFR1/TNFR2 KO mice, and they were further inhibited in enalapril-treated TNFR1/TNFR2 KO mice. Incapacitating the angiotensin II or the TNF-alpha 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.
引用
收藏
页码:F777 / F785
页数:9
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