Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice
Yutaka Hisada, Takeshi Sugaya, Masaya Yamanouchi, Hiromi Uchida, Hisako Fujimura, Hiroaki Sakurai, Akiyoshi Fukamizu, Kazuo Murakami
Yutaka Hisada, Takeshi Sugaya, Masaya Yamanouchi, Hiromi Uchida, Hisako Fujimura, Hiroaki Sakurai, Akiyoshi Fukamizu, Kazuo Murakami
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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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Changes in urinary protein excretion after the administration of anti-GB...
Changes in urinary protein excretion after the administration of anti-GBM AS. Urinary protein excretion was measured in the mice sacrificed at day 126. The open circles and closed circles represent the AT1a+/+ and AT1a–/– mice, respectively. The open squares with a dotted line and the closed squares with a dotted line represent the physiological protein excretion of the AT1a+/+ and AT1a–/– mice, respectively. Data are mean ± SE. Statistical significance was evaluated by comparing the data of the AT1a–/– mice with those of the AT1a+/+ mice at each time point. **P < 0.01.