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

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

  • Cell Rep. 2024 Apr 23;43(4):114075. doi: 10.1016/j.celrep.2024.114075.
Dandan Zhong 1,  Jingshuo Chen 1,  Ranran Qiao 2,  Chang Song 3,  Chang Hao 3,  Yingying Zou 1,  Mi Bai 4,  Wen Su 5,  Baoxue Yang 6,  Dong Sun 7,  Zhanjun Jia 8,  Ying Sun 9
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China.
  • 2 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.
  • 3 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.
  • 4 Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China.
  • 5 Department of Pathophysiology, Shenzhen University, Shenzhen 518060, China; Shenzhen University Health Science Center, Shenzhen University, Shenzhen 518060, China.
  • 6 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.
  • 7 Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, 99 West Huai-hai Road, Xuzhou, Jiangsu 221002, China. Electronic address: [email protected].
  • 8 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. Electronic address: [email protected].
  • 9 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China. Electronic address: [email protected].
PMID: 38583151 DOI: 10.1016/j.celrep.2024.114075
Abstract

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.

Keywords

CP: Metabolism; CP: Molecular biology; FABP5; Rev-Erbα; diabetic kidney disease; lipid accumulation; mPGES-2.

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