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
  • 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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