Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cell Death Dis. 2021 Oct 30;12(11):1031. doi: 10.1038/s41419-021-04326-y.
Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but the precise mechanism is not fully understood. Whether lipophagy, a selective type of autophagy participates in renal ectopic lipid deposition (ELD) and lipotoxicity in the kidney of DN is unknown. Here, decreased lipophagy, increased ELD and lipotoxcity were observed in tubular cells of patients with DN, which were accompanied with reduced expression of AdipoR1 and p-AMPK. Similar results were found in db/db mice, these changes were reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, a significantly decreased level of lipophagy was observed in HK-2 cells, a human proximal tubular cell line treated with high glucose, which was consistent with increased lipid deposition, apoptosis and fibrosis, while were partially alleviated by AdipoRon. However, these effects were abolished by pretreatment with ULK1 inhibitor SBI-0206965, autophagy inhibitor chloroquine and enhanced by AMPK activator AICAR. These data suggested by the first time that autophagy-mediated lipophagy deficiency plays a critical role in the ELD and lipid-related renal injury of DN.
自噬介导的脂毒性在糖尿病肾病 (DN) 的进展中起着关键作用，但确切的机制尚不完全清楚。脂噬，一种选择性自噬，是否参与 DN 肾脏中的肾脏异位脂质沉积 (ELD) 和脂毒性尚不清楚。在这里，在 DN 患者的肾小管细胞中观察到自噬减少、ELD 和脂毒性增加，同时伴有 AdipoR1 和 p-AMPK 表达减少。db/db 小鼠中也发现了类似的结果，这些变化在 AdipoRon 处理后得到逆转，AdipoRon 是一种促进自噬的脂联素受体激活剂。此外，在高糖处理的人近端肾小管细胞系 HK-2 细胞中，观察到脂噬显著减少，这与脂质沉积、细胞凋亡和纤维化增加一致，而 AdipoRon 部分缓解了这些变化。然而，这些作用被 ULK1 抑制剂 SBI-0206965、自噬抑制剂氯喹预处理所消除，并被 AMPK 激活剂 AICAR 增强。这些数据首次表明，自噬介导的脂噬不足在 DN 的 ELD 和与脂质相关的肾脏损伤中起着关键作用。
