Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China.
Mol Med. 2022 Sep 23;28(1):117. doi: 10.1186/s10020-022-00545-x.
Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD.
Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2 mice) and the control mice (Pacs-2 mice). Transcriptomic analysis was performed between Pacs-2 mice and PT-Pacs-2 mice.
Diabetic PT-Pacs-2 mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2 mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2 mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA.
PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling.
管状细胞中的脂质积累在糖尿病肾病（DKD）中起着关键作用。针对脂质代谢紊乱的治疗在延缓 DKD 进展方面具有临床价值，但分子介导脂质相关肾损伤的确切机制尚不清楚。磷酸化富磷簇分选蛋白 2（PACS-2）是一种多功能分选蛋白，在脂质代谢中发挥作用。本研究旨在确定 PACS-2 在 DKD 中脂质相关肾损伤中的作用。
通过高脂肪饮食联合腹腔注射链脲佐菌素（HFD/STZ）在近端肾小管特异性敲除 Pacs-2 小鼠（PT-Pacs-2 小鼠）和对照小鼠（Pacs-2 小鼠）中诱导糖尿病。对 Pacs-2 小鼠和 PT-Pacs-2 小鼠进行转录组分析。
与 Pacs-2 小鼠相比，糖尿病 PT-Pacs-2 小鼠的肾小管损伤和蛋白尿更为严重，同时伴随着脂质合成、摄取增加，胆固醇流出减少以及肾脏小管内脂质堆积。此外，转录组分析显示，对照 PT-Pacs-2 小鼠肾脏中固醇 O-酰基转移酶 1（Soat1）的 mRNA 水平上调。在高糖+棕榈酸（HGPA）条件下，HK2 细胞中 PACS-2 的 siRNA 转染加重了脂质沉积，并增加了 SOAT1 和固醇调节元件结合蛋白（SREBPs）的表达，而共转染 SOAT1 siRNA 部分阻断了这一作用。
PACS-2 通过 SOAT1/SREBPs 信号通路对 DKD 中的脂质相关肾损伤具有保护作用。
