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Excess aldosterone is a critical danger signal for inflammasome activation in the development of renal fibrosis in mice
- Source :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 29(9)
- Publication Year :
- 2015
-
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.
- Subjects :
- Male
medicine.medical_specialty
Inflammasomes
Interleukin-1beta
Caspase 1
Biology
Biochemistry
Proinflammatory cytokine
chemistry.chemical_compound
Mice
Mineralocorticoid receptor
Fibrosis
Internal medicine
Genetics
medicine
Renal fibrosis
Animals
Molecular Biology
Aldosterone
Mice, Knockout
Kidney
Macrophages
Interleukin-18
Inflammasome
medicine.disease
CARD Signaling Adaptor Proteins
Enzyme Activation
Endocrinology
medicine.anatomical_structure
chemistry
Gene Expression Regulation
Kidney Diseases
Apoptosis Regulatory Proteins
Reactive Oxygen Species
Biotechnology
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 15306860
- Volume :
- 29
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Accession number :
- edsair.doi.dedup.....28d42cd9038798c34ec85a91aeadf96d