Atgl deficiency induces podocyte apoptosis and leads to glomerular filtration barrier damage
Atgl deficiency induces podocyte apoptosis and leads to glomerular filtration barrier damage
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Atgl 缺陷诱导足细胞凋亡并导致肾小球滤过屏障损伤
DOI：
10.1111/febs.14038
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发表时间：
2017-04-01
期刊：
影响因子：
5.4
通讯作者：
Chen, Bing
中科院分区：
文献类型：
--
作者：
Chen, Wen;Jiang, Youzhao;Chen, Bing
脂质代谢异常、肾脏脂质蓄积和脂毒性与肾小球病的病理特征相关。然而，脂质积累导致这种疾病发生或进展的机制尚未完全阐明。在这项工作中，我们确定了脂肪分解中的限速酶脂肪甘油三酯脂肪酶（ATGL；也称为含 patatin 样磷脂酶结构域的蛋白 2）、肾脂质代谢和肾脏疾病中的作用。 ATGL缺陷型（Atgl(−/−)）小鼠表现出蛋白尿，并伴有肾脏中脂肪的异位沉积。磁共振成像表明造影剂钆喷酸保留在肾组织中，表明肾小球滤过屏障存在缺陷。此外，透射电子显微镜显示足细胞中存在脂质沉积，以及足突融合和提示细胞凋亡的形态变化。事实上，shRNA 介导的 ATGL 消耗促进了足细胞凋亡，并伴随着细胞内活性氧 (ROS) 和 F-肌动蛋白纤维重新分布水平的增加。通过抗氧化剂 N-乙酰半胱氨酸治疗可以部分逆转这些影响。这些数据表明，ATGL 缺乏会诱导肾脂质积累、蛋白尿和肾小球滤过屏障功能障碍，并暗示细胞内 ROS 水平升高会诱导足细胞 F-肌动蛋白重排、足突融合和细胞凋亡，而这些病理特征是这些病理特征的基础。
Abnormal lipid metabolism, renal lipid accumulation and lipotoxicity are associated with the pathological features of glomerulopathy. However, the mechanisms by which lipid accumulation leads to the development or progression of this disease have not been fully elucidated. In this work, we have identified a role for the rate‐limiting enzyme in lipolysis, adipose triglyceride lipase (ATGL; also called patatin‐like phospholipase domain‐containing protein 2), in renal lipid metabolism and kidney disease. ATGL‐deficient (Atgl(−/−)) mice displayed albuminuria, accompanied by ectopic deposition of fat in the kidney. Magnetic resonance imaging demonstrated that the contrast agent gadopentetic acid was retained in kidney tissue, suggesting defects in the glomerular filtration barrier. Furthermore, transmission electron microscopy revealed lipid deposits in the podocyte, along with foot process fusion and morphological changes suggestive of apoptosis. Indeed, shRNA‐mediated depletion of ATGL promoted podocyte apoptosis, accompanied by increased levels of intracellular reactive oxygen species (ROS) and F‐actin fibre redistribution. These effects could be partially reversed by treatment with the antioxidant N‐acetylcysteine. These data suggest that ATGL deficiency induces renal lipid accumulation, proteinuria and glomerular filtration barrier dysfunction and implicate increased intracellular ROS levels in inducing podocyte F‐actin rearrangement, foot process fusion and apoptosis that underlie these pathological features.