Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China.
Ren Fail. 2022 Dec;44(1):902-913. doi: 10.1080/0886022X.2022.2079524.
Although recent studies have indicated that mutations in the gene encoding diacylglycerol kinase epsilon (DGKE) result in some proteinuria related hereditary kidney diseases, the DGKE expression pattern in the kidney and its contribution to acute kidney injury (AKI) remain unknown. Therefore, the present study was designed to detect the role of DGKE in mice with AKI. DGKE expression was time-dependently altered in the kidneys of mice with renal ischemia/reperfusion injury (IRI). Compared with wild-type (WT) mice, DGKE- overexpressing mice () exhibited protective effects against renal IRI, including reduced serum creatinine, blood urea concentration, tubular cell death and inflammatory responses as well as improved morphological injuries. Consistently, , DGKE overexpression in human renal proximal tubule (HK-2) cells also protected against oxygen-glucose deprivation (OGD)/reoxygenation-induced cell death. Mechanistically, DGKE regulated Klotho expression, at least partly the transcription factor Krüppel-like factor (KLF) 15. Moreover, a significant reduction in DGKE was also found in kidneys from patients with ischemia-associated acute tubular necrosis (ATN). Collectively, our studies demonstrate that DGKE protects against AKI in mice at least partly through KLF15/Klotho signaling pathway, indicating that DGKE may present an innovative therapeutic strategy for treating patients with AKI.
虽然最近的研究表明，二酰基甘油激酶 ε（DGKE）基因编码突变会导致一些与蛋白尿相关的遗传性肾脏疾病，但 DGKE 在肾脏中的表达模式及其对急性肾损伤（AKI）的贡献仍不清楚。因此，本研究旨在检测 DGKE 在 AKI 小鼠中的作用。肾缺血/再灌注损伤（IRI）小鼠肾脏中 DGKE 的表达呈时间依赖性改变。与野生型（WT）小鼠相比，DGKE 过表达小鼠（）对肾 IRI 具有保护作用，包括血清肌酐、血尿素浓度、肾小管细胞死亡和炎症反应降低以及形态损伤改善。一致地，在人肾近端小管（HK-2）细胞中过表达 DGKE 也能抵抗氧葡萄糖剥夺（OGD）/再氧合诱导的细胞死亡。在机制上，DGKE 调节 Klotho 表达，至少部分通过转录因子 Krüppel-like factor 15（KLF15）。此外，在与缺血相关的急性肾小管坏死（ATN）患者的肾脏中也发现 DGKE 显著减少。总之，我们的研究表明，DGKE 通过 KLF15/Klotho 信号通路至少部分保护小鼠免受 AKI，表明 DGKE 可能为治疗 AKI 患者提供一种创新的治疗策略。
