Diacylglycerol kinase epsilon protects against renal ischemia/reperfusion injury in mice through Krüppel-like factor 15/klotho pathway.
Diacylglycerol kinase epsilon protects against renal ischemia/reperfusion injury in mice through Krüppel-like factor 15/klotho pathway.
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二酰基甘油激酶Epsilon通过Krüppel样因子15/klotho途径预防小鼠的肾脏缺血/再灌注损伤。
DOI：
10.1080/0886022x.2022.2079524
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发表时间：
2022-12
期刊：
影响因子：
3
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中科院分区：
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尽管最近的研究表明编码二酰基甘油激酶epsilon （DGKE）的基因突变可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）的影响尚不清楚。因此，本研究旨在检测DGKE在AKI小鼠中的作用。DGKE在肾缺血再灌注损伤（IRI）小鼠肾脏中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（Rosa26-Dgke+/+）对肾IRI表现出保护作用，包括降低血清肌酐、血尿素浓度、小管细胞死亡和炎症反应，以及改善形态学损伤。与此一致的是，在体外，DGKE在人肾近端小管（HK-2）细胞中的过表达也可以保护氧-葡萄糖剥夺(OGD)/再氧诱导的细胞死亡。从机制上讲，DGKE至少部分通过转录因子kr<s:1> ppel样因子（KLF） 15调节Klotho的表达。此外，在缺血相关性急性肾小管坏死（ATN）患者的肾脏中也发现DGKE显著减少。总的来说，我们的研究表明DGKE至少部分通过KLF15/Klotho信号通路保护小鼠抗AKI，这表明DGKE可能为治疗AKI患者提供一种创新的治疗策略。
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 (Rosa26-Dgke+/+) 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, in vitro, 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 via 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.