Selective estrogen receptor modulation attenuates proteinuria-induced renal tubular damage by modulating mitochondrial oxidative status
Selective estrogen receptor modulation attenuates proteinuria-induced renal tubular damage by modulating mitochondrial oxidative status
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DOI：
10.1038/ki.2012.475
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发表时间：
2013-04-01
影响因子：
19.6
通讯作者：
Kashihara, Naoki
中科院分区：
文献类型：
--
作者：
Nishi, Yuko;Satoh, Minoru;Kashihara, Naoki
蛋白尿是进行性肾脏疾病的独立危险因素，因为它启动或加重了肾小管间质损伤。在临床上，女性对慢性肾脏疾病的进展不太敏感；然而，雌激素受体刺激的肾脏保护作用的机制尚未阐明。最近发现，游离脂肪酸可以触发依赖炎症体的炎症反应，而这种反应需要线粒体衍生的活性氧物种。白蛋白结合的游离脂肪酸通过在体外培养的人近端小管上皮细胞中产生线粒体活性氧类来激活炎症体，雷洛昔芬可抑制这一作用。雌性ICR来源的肾小球肾炎小鼠(遗传性肾病综合征小鼠)摘除卵巢，给予选择性雌激素受体调节剂雷洛昔芬治疗。去卵巢的小鼠表现出管状炎性小体的激活和炎性小体依赖的细胞因子水平升高。雷洛昔芬减轻了这些改变，改善了肾小管间质损伤，减少了活性氧的产生，避免了形态变化，并改善了线粒体的呼吸功能。在线粒体β-氧化途径中编码限速酶的基因的表达被卵巢切除所减少，但被雷洛昔芬增强。因此，炎性小体可能成为治疗蛋白尿性肾损伤的一种新的、有前景的靶点。《国际肾脏》(2013年)83,662-673；doi：10.1038/ki.2012.475；2013年1月23日在线发布
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