Genetic or pharmacologic blockade of mPGES-2 attenuates renal lipotoxicity and diabetic kidney disease by targeting Rev-Erbα/FABP5 signaling
Dandan Zhong,
Jingshuo Chen,
Ranran Qiao,
Chang Song,
Chang Hao,
Yingying Zou,
Mi Bai,
Wen Su,
Baoxue Yang,
Dong Sun,
Zhanjun Jia,
Ying Sun
Affiliations
Dandan Zhong
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
Jingshuo Chen
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
Ranran Qiao
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China; Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China; Public Experimental Research Center of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
Chang Song
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China; Public Experimental Research Center of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
Chang Hao
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China; Public Experimental Research Center of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
Yingying Zou
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
Mi Bai
Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
Wen Su
Department of Pathophysiology, Shenzhen University, Shenzhen 518060, China; Shenzhen University Health Science Center, Shenzhen University, Shenzhen 518060, China
Baoxue Yang
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China; State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Dong Sun
Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, 99 West Huai-hai Road, Xuzhou, Jiangsu 221002, China; Corresponding author
Zhanjun Jia
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China; Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China; Corresponding author
Ying Sun
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China; Corresponding author
Summary: 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.
