Genetic or pharmacologic blockade of mPGES-2 attenuates renal lipotoxicity and diabetic kidney disease by targeting Rev-Erbα/FABP5 signaling

作者：Dandan Zhong, Jingshuo Chen, Ranran Qiao, Chang Myeon Song, Chang Hao, Yingying Zou, Mi Bai, Wen Su, Baoxue Yang, Dong Sun, Zhanjun Jia, Ying Sun · 发表于：Cell Reports · 年份：2024 · DOI：10.1016/j.celrep.2024.114075 · 被引用次数：11 · 研究领域：Diabetes Treatment and Management、Cholesterol and Lipid Metabolism、Peroxisome Proliferator-Activated Receptors

Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and no specific drugs are clinically available. We have previously demonstrated that inhibiting microsomal prostaglandin E synthase-2 (mPGES-2) alleviated type 2 diabetes by enhancing β cell function and promoting insulin production. However, the involvement of mPGES-2 in DKD remains unclear. Here, we aimed to analyze the association of enhanced mPGES-2 expression with impaired metabolic homeostasis of renal lipids and subsequent renal damage. Notably, global knockout or pharmacological blockage of mPGES-2 attenuated diabetic podocyte injury and tubulointerstitial fibrosis, thereby ameliorating lipid accumulation and lipotoxicity. These findings were further confirmed in podocyte- or tubule-specific mPGES-2-deficient mice. Mechanistically, mPGES-2 and Rev-Erbα competed for heme binding to regulate fatty acid binding protein 5 expression and lipid metabolism in the diabetic kidney. Our findings suggest a potential strategy for treating DKD via mPGES-2 inhibition.