Diacylglycerol kinase epsilon protects against renal ischemia/reperfusion injury in mice through Krüppel-like factor 15/klotho pathway

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.