Ren Linan, Cui Haiying, Wang Yao, Ju Feng, Cai Yunjia, Gang Xiaokun, Wang Guixia
Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China; Institute of Translational Medicine, First Hospital of Jilin University, Changchun 130021, Jilin, China.
Department of Orthopedics, The Second Hospital of Jilin University, Changchun 130021, Jilin, China.
Biomed Pharmacother. 2023 May;161:114465. doi: 10.1016/j.biopha.2023.114465. Epub 2023 Mar 3.
Lipotoxicity is the dysregulation of the lipid environment and/or intracellular composition that leads to accumulation of harmful lipids and ultimately to organelle dysfunction, abnormal activation of intracellular signaling pathways, chronic inflammation and cell death. It plays an important role in the development of acute kidney injury and chronic kidney disease, including diabetic nephropathy, obesity-related glomerulopathy, age-related kidney disease, polycystic kidney disease, and the like. However, the mechanisms of lipid overload and kidney injury remain poorly understood. Herein, we discuss two pivotal aspects of lipotoxic kidney injury. First, we analyzed the mechanism of lipid accumulation in the kidney. Accumulating data indicate that the mechanisms of lipid overload in different kidney diseases are inconsistent. Second, we summarize the multiple mechanisms by which lipotoxic species affect the kidney cell behavior, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, dysregulated autophagy, and inflammation, highlighting the central role of oxidative stress. Blocking the molecular pathways of lipid accumulation in the kidney and the damage of the kidney by lipid overload may be potential therapeutic targets for kidney disease, and antioxidant drugs may play a pivotal role in the treatment of kidney disease in the future.
脂毒性是脂质环境和/或细胞内成分的失调，导致有害脂质积累，最终导致细胞器功能障碍、细胞内信号通路异常激活、慢性炎症和细胞死亡。它在急性肾损伤和慢性肾病的发生发展中起重要作用，包括糖尿病肾病、肥胖相关肾小球病、年龄相关性肾病、多囊肾病等。然而，脂质过载和肾损伤的机制仍知之甚少。在此，我们讨论脂毒性肾损伤的两个关键方面。首先，我们分析了肾脏中脂质积累的机制。越来越多的数据表明，不同肾脏疾病中脂质过载的机制并不一致。其次，我们总结了脂毒性物质影响肾细胞行为的多种机制，包括氧化应激、内质网应激、线粒体功能障碍、自噬失调和炎症，强调了氧化应激的核心作用。阻断肾脏中脂质积累的分子途径以及脂质过载对肾脏的损害可能是肾病的潜在治疗靶点，抗氧化药物可能在未来肾病治疗中发挥关键作用。
