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Excess aldosterone is a critical danger signal for inflammasome activation in the development of renal fibrosis in mice
Author(s) -
Kadoya Hiroyuki,
Satoh Minoru,
Sasaki Tamaki,
Taniguchi Shun'ichiro,
Takahashi Masafumi,
Kashihara Naoki
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-271734
Subject(s) - inflammasome , aldosterone , inflammation , reactive oxygen species , proinflammatory cytokine , fibrosis , endocrinology , medicine , kidney , chemistry , caspase 1 , kidney disease , biochemistry
High levels of aldosterone impair renal function by activating proinflammatory and profibrotic pathways. However, the molecular mechanism underlying aldosterone‐induced inflammation and fibrosis is unknown. Inflammasome activation contributes to chronic kidney disease. We hypothesized that aldosterone induces renal tubulointerstitial inflammation and fibrosis by activating the inflammasome. Infusing wild‐type mice with aldosterone (0.25 mg/kg/d) caused tubulointerstitial damage, increased expression of inflammasome components, caspase 1 activation, and overproduction of IL‐1β and IL‐18. These changes were suppressed by eplerenone treatment (100 mg/kg/d) in wild‐type mice or in mice deficient in apoptosis‐associated speck‐like protein with a caspase‐recruitment domain (ASC). Caspase 1‐positive and F4/80‐positive cells colocalized in the interstitium. Bone marrow transplantation using ASC‐deficient mice indicated that inflammasome activation in macrophages mediated aldosterone‐induced renal fibrosis. IL‐18 was detected in culture supernatants of macrophages treated with aldosterone, and mitochondria‐derived reactive oxygen species activated the inflammasome in these macrophages. Our results indicate that exposure of macrophages to high levels of aldosterone resulted in the activation of inflammasomes via the mitochondria‐derived reactive oxygen species. Thus, inflammasome activation in macrophages may serve as a new therapeutic target for chronic kidney disease.—Kadoya, H., Satoh, M., Sasaki, T., Taniguchi, S., Takahashi, M., Kashihara, N. Excess aldosterone is a critical danger signal for inflammasome activation in the development of renal fibrosis in mice. FASEB J. 29, 3899‐3910 (2015). www.fasebj.org