Journal
KIDNEY INTERNATIONAL
Volume 83, Issue 4, Pages 662-673Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2012.475
Keywords
beta-oxidation; free fatty acid; inflammasome; mitochondrial stress
Categories
Funding
- Kidney Foundation, Japan [JKFB08-27]
- Grants-in-Aid for Scientific Research [24390218, 22590920, 23591209] Funding Source: KAKEN
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Proteinuria is an independent risk factor for progressive renal diseases because it initiates or aggravates tubulointerstitial injury. Clinically, females are less susceptible to progression of chronic kidney disease; however, the mechanisms underlying the renoprotective effect of estrogen receptor stimulation have yet to be clarified. Recently, inflammasome-dependent inflammatory responses were shown to be triggered by free fatty acids, and mitochondria-derived reactive oxygen species were shown to be required for this response. Albumin-bound free fatty acids trigger inflammasome activation through mitochondrial reactive oxygen species production in human proximal tubule epithelial cells in vitro, an effect inhibited by raloxifene. Female ICR-derived glomerulonephritic mice (mice with hereditary nephritic syndrome) were ovariectomized and treated with raloxifene, a selective estrogen receptor modulator. Ovariectomized mice showed activation of tubular inflammasomes and elevated levels of inflammasome-dependent cytokines. Raloxifene attenuated these changes ameliorating tubulointerstitial damage, reduced production of reactive oxygen species, averted morphological changes, and improved respiratory function in mitochondria. The expression of genes that encode rate-limiting enzymes in the mitochondrial beta-oxidation pathway was reduced by ovariectomy but enhanced by raloxifene. Thus, inflammasomes may be a novel and promising therapeutic target for proteinuria-induced renal injury. Kidney International (2013) 83, 662-673; doi:10.1038/ki.2012.475; published online 23 January 2013
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