11292619

pubmed:Citation

5

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 (Vv(int)) in the C57BI/6 wild-type mouse was decreased in the AT(1a) 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 Vv(int) 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.

eng

IM

MEDLINE

1931-857X

Print

NLM

F777-85

pubmed-meshheading:11292619-Actins, pubmed-meshheading:11292619-Angiotensin II, pubmed-meshheading:11292619-Angiotensin-Converting Enzyme Inhibitors, pubmed-meshheading:11292619-Animals, pubmed-meshheading:11292619-Antigens, CD, pubmed-meshheading:11292619-Collagen, pubmed-meshheading:11292619-Enalapril, pubmed-meshheading:11292619-Enzyme-Linked Immunosorbent Assay, pubmed-meshheading:11292619-Fibrosis, pubmed-meshheading:11292619-Kidney, pubmed-meshheading:11292619-Lymphotoxin-alpha, pubmed-meshheading:11292619-Mice, pubmed-meshheading:11292619-Mice, Inbred C57BL, pubmed-meshheading:11292619-Mice, Knockout, pubmed-meshheading:11292619-Microscopy, Electron, pubmed-meshheading:11292619-Muscle, Smooth, pubmed-meshheading:11292619-RNA, Messenger, pubmed-meshheading:11292619-Receptors, Tumor Necrosis Factor, pubmed-meshheading:11292619-Receptors, Tumor Necrosis Factor, Type I, pubmed-meshheading:11292619-Receptors, Tumor Necrosis Factor, Type II, pubmed-meshheading:11292619-Tumor Necrosis Factor-alpha, pubmed-meshheading:11292619-Ureteral Obstruction

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

Journal Article, Research Support, U.S. Gov't, P.H.S.