Farnesoid X Receptor Protects against Kidney Injury in Uninephrectomized Obese Mice
Farnesoid X Receptor Protects against Kidney Injury in Uninephrectomized Obese Mice
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DOI：
10.1074/jbc.m115.694323
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发表时间：
2016-01-29
影响因子：
4.8
通讯作者：
Kullak-Ublick, Gerd A.
中科院分区：
文献类型：
--
作者：
Gai, Zhibo;Gui, Ting;Kullak-Ublick, Gerd A.
法尼醇X受体（FXR）的激活表明这种核胆汁酸受体在预防糖尿病肾病和肥胖引起的肾损伤中具有治疗潜力。在这里，我们研究了FXR对接受单侧肾切除术的小鼠中肥胖诱导的肾损伤的保护作用，该模型类似于肥胖个体肾脏捐赠的临床情况。高脂饮食喂养的小鼠出现代谢综合征的核心特征，随后出现肾脂质蓄积和肾损伤，包括肾小球硬化、间质纤维化和蛋白尿。单肾切除术加重了这种影响。在人类肾活检中，4-羟基壬烯醛（4-HNE），葡萄糖调节蛋白78（Grp 78）和C/EBP同源蛋白，内质网应激标志物的染色，在15例肥胖患者的近端小管中比16例非肥胖患者更突出。在用FXR激动剂奥贝胆酸处理的小鼠中，肾损伤、肾脂质积聚、细胞凋亡和脂质过氧化变化减弱。此外，紊乱的线粒体功能得到改善，线粒体呼吸链恢复后奥贝胆酸治疗。培养肾近端小管细胞与游离脂肪酸和FXR激动剂表明，FXR活化保护细胞免受游离脂肪酸诱导的氧化应激和内质网应激，如活性氧染色和Grp 78免疫染色水平的降低所示。参与谷胱甘肽代谢的几个基因在残肾中被FXR激活诱导，这与谷胱甘肽二硫化物/谷胱甘肽比率降低一致。总之，FXR激活维持内源性谷胱甘肽稳态并保护单侧肾切除小鼠的肾脏免受肥胖诱导的损伤。
Activation of the farnesoid X receptor (FXR) has indicated a therapeutic potential for this nuclear bile acid receptor in the prevention of diabetic nephropathy and obesity-induced renal damage. Here, we investigated the protective role of FXR against kidney damage induced by obesity in mice that had undergone uninephrectomy, a model resembling the clinical situation of kidney donation by obese individuals. Mice fed a high-fat diet developed the core features of metabolic syndrome, with subsequent renal lipid accumulation and renal injury, including glomerulosclerosis, interstitial fibrosis, and albuminuria. The effects were accentuated by uninephrectomy. In human renal biopsies, staining of 4-hydroxynonenal (4-HNE), glucose-regulated protein 78 (Grp78), and C/EBP-homologous protein, markers of endoplasmic reticulum stress, was more prominent in the proximal tubules of 15 obese patients compared with 16 non-obese patients. In mice treated with the FXR agonist obeticholic acid, renal injury, renal lipid accumulation, apoptosis, and changes in lipid peroxidation were attenuated. Moreover, disturbed mitochondrial function was ameliorated and the mitochondrial respiratory chain recovered following obeticholic acid treatment. Culturing renal proximal tubular cells with free fatty acid and FXR agonists showed that FXR activation protected cells from free fatty acid-induced oxidative stress and endoplasmic reticulum stress, as denoted by a reduction in the level of reactive oxygen species staining and Grp78 immunostaining, respectively. Several genes involved in glutathione metabolism were induced by FXR activation in the remnant kidney, which was consistent with a decreased glutathione disulfide/glutathione ratio. In summary, FXR activation maintains endogenous glutathione homeostasis and protects the kidney in uninephrectomized mice from obesity-induced injury.