Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice
Yutaka Hisada, … , Akiyoshi Fukamizu, Kazuo Murakami
Yutaka Hisada, … , Akiyoshi Fukamizu, Kazuo Murakami
Published March 1, 1999
Citation Information: J Clin Invest. 1999;103(5):627-635. https://doi.org/10.1172/JCI2454.
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Article

Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice

Abstract

Several lines of evidence show the importance of angiotensin II (AII) in renal injuries, especially when hemodynamic abnormalities are involved. To elucidate the role of AII in immune-mediated renal injury, we studied anti–glomerular basement membrane (GBM) nephritis in AII type 1a receptor (AT1a)–deficient homozygous (AT1a–/–) and wild-type (AT1a+/+) mice. A transient activation of the renin–angiotensin system (RAS) was observed in both groups of mice at around day 1. A renal expression of monocyte chemoattractant protein-1 (MCP-1) was transiently induced at six hours in both groups, which was then downregulated at day 1. In the AT1a+/+ mice, after RAS activation, the glomerular expression of MCP-1 was exacerbated at days 7 and 14. Thereafter, severe proteinuria developed, and the renal expressions of transforming growth factor-β1 (TGF-β1) and collagen type I increased, resulting in severe glomerulosclerosis and interstitial fibrosis. In contrast, glomerular expression of MCP-1, proteinuria, and tissue damage were markedly ameliorated in the AT1a–/– mice. Because this amelioration is likely due to the lack of AT1a, we can conclude that AII action, mediated by AT1a, plays a pathogenic role in anti-GBM nephritis, in which AII may contribute to the exacerbation of glomerular MCP-1 expression. These results suggest the involvement of AII in immune-mediated renal injuries.

Authors

Yutaka Hisada, Takeshi Sugaya, Masaya Yamanouchi, Hiromi Uchida, Hisako Fujimura, Hiroaki Sakurai, Akiyoshi Fukamizu, Kazuo Murakami

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Activation of the RAS after administration of anti-GBM AS. Mice were sac...
Activation of the RAS after administration of anti-GBM AS. Mice were sacrificed at 6 h and days 1, 7, and 14 after the administration of anti-GBM AS. (a) The amount of active renin in the plasma was estimated by RIA as described in the Methods. (b) The expression of the angiotensinogen mRNA in the liver was examined by Northern blot analysis. Open circles represent the AT1a+/+ mice, and closed circles represent the AT1a–/– mice. (c) Renal expressions of AT1a mRNA in the AT1a+/+ mice and lacZ mRNA in the AT1a–/– mice. Open circles and closed circles represent the gene expressions of AT1a and lacZ, respectively. Results at each time point in b and c were given as the fold increase compared with those observed before the induction of nephritis (day 0). (d) Changes in the MBP. Open circles represent the AT1a+/+ mice, and closed circles represent the AT1a–/– mice. Data are mean ± SE. Statistical significance was evaluated by comparing the data at each time point with those obtained before the administration of anti-GBM AS (day 0). *P < 0.05, **P < 0.01. AI, angiotension I; AS, antiserum; AT1a, angiotensin II type 1a receptor; AT1a+/+mice, AT1a wild-type mice; GBM, glomerular basement membrane; MBP, mean blood pressure; RAS, renin–angiotensin system.