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

Abstract

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.

Protective effects of curcumin on kidney tissue in ischemia-reperfusion injury in rats

“…Although significant progress has been made in understanding the pathophysiology of kidney injury, it has not been fully clarified, and despite attempts to develop treatment methods, it remains a destructive disease with high mortality and morbidity rates all over the world [7]. Renal damage caused by IR typically arises following hypotension, hemorrhagic shock, major cardiovascular surgery, and transplants [8].…”

Roles of Krüppel-Like Transcription Factors KLF6 and KLF15 in Proximal Tubular Metabolism

“…The pathway by which KLF15 is downregulated in AKI is not known. However, in IRI, the decreased KLF15 expression was partially negated by overexpression of diacylglycerol kinase epsilon, highlighting a potential link between diacylglycerol/phosphatidic acid intracellular signaling and regulation of KLF15 expression [13].…”