Selective estrogen receptor modulation attenuates proteinuria-induced renal tubular damage by modulating mitochondrial oxidative status.
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 β-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.
Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.
Yuko
Y
Nishi
Minoru
M
Satoh
Hajime
H
Nagasu
Hiroyuki
H
Kadoya
Chieko
C
Ihoriya
Kengo
K
Kidokoro
Tamaki
T
Sasaki
Naoki
N
Kashihara
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001284:Atrophy; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009394:Nephritis, Hereditary / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011507:Proteinuria / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*
D016207:Cytokines; D058847:Inflammasomes; D018836:Inflammation Mediators; D016328:NF-kappa B; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride