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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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Figure 4

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Expression of MCP-1. (a) Gene expression of MCP-1 during the first 14 da...
Expression of MCP-1. (a) Gene expression of MCP-1 during the first 14 days after the anti-GBM AS administration was examined by Northern blot analysis. Total RNA from mice at day 0 (control), 6 h, and days 1, 7, and 14 was separated on an agarose gel and probed for MCP-1. The blots were stripped and rehybridized with a cDNA probe for the 28S rRNA. Two representative results of each animal group were shown. (b) The gene expression of MCP-1 was estimated as described in Methods. The closed bars represent the AT1a+/+ mice, and the hatched bars represent the AT1a–/– mice. Data are mean ± SE in arbitrary units. *P < 0.05 compared with the AT1a+/+ mice. (c) Immunoperoxidase staining for MCP-1 at day 7 after anti-GBM AS administration. In the AT1a+/+ mice, MCP-1 expression was propagated in the glomeruli. In contrast, MCP-1 expression was reduced in the AT1a–/– mice. ×200. MCP-1, monocyte chemoattractant protein-1.