title: Contributions of angiotensin II and tumor necrosis factor-alpha to the development of renal fibrosis.
abstract: 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.
authors: Departments of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, 216 S. Kingshighway Blvd., St. Louis, Missouri 63110-1092, USA.
authors: G
authors: G
authors: Guo
authors: J
authors: J
authors: Morrissey
authors: R
authors: R
authors: McCracken
authors: T
authors: T
authors: Tolley
authors: H
authors: H
authors: Liapis
authors: S
authors: S
authors: Klahr
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000804:Angiotensin II / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D004656:Enalapril / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis; D007668:Kidney / Q000473:pathology* / Q000648:ultrastructure; D008233:Lymphotoxin-alpha / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009130:Muscle, Smooth / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014517:Ureteral Obstruction / Q000473:pathology
chemical_list: D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D015703:Antigens, CD; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D004656:Enalapril; D003094:Collagen