title: Excess aldosterone is a critical danger signal for inflammasome activation in the development of renal fibrosis in mice.
abstract: 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.
authors.affiliation: *Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan; Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; and Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kadoya
authors.affiliation: *Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan; Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; and Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan msatoh@med.kawasaki-m.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.affiliation: *Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan; Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; and Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: *Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan; Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; and Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.affiliation: *Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan; Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; and Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: *Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan; Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; and Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kashihara
mesh_terms: D000450:Aldosterone / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; C587672:IL1B protein, mouse; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C498534:Pycard protein, mouse; D017382:Reactive Oxygen Species; D000450:Aldosterone; D020170:Caspase 1
keywords: chronic inflammation; kidney; mineralocorticoid receptor; mitochondria; reactive oxygen species