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

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 ß 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.

Targeting mPGES-2 to protect against acute kidney injury via inhibition of ferroptosis dependent on p53.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality but no specific therapy. Microsomal prostaglandin E synthase-2 (mPGES-2) is a PGE2 synthase but can metabolize PGH2 to malondialdehyde by forming a complex with heme. However, the role and mechanism of action of mPGES-2 in AKI remain unclear. To examine the role of mPGES-2, both global and tubule-specific mPGES-2-deficient mice were treated with cisplatin to induce AKI. mPGES-2 knockdown or overexpressing HK-2 cells were exposed to cisplatin to cause acute renal tubular cell injury. The mPGES-2 inhibitor SZ0232 was used to test the translational potential of targeting mPGES-2 in treating AKI. Additionally, mice were subjected to unilateral renal ischemia/reperfusion to further validate the effect of mPGES-2 on AKI. Interestingly, both genetic and pharmacological blockage of mPGES-2 led to decreased renal dysfunction and morphological damage induced by cisplatin and unilateral renal ischemia/reperfusion. Mechanistic exploration indicated that mPGES-2 deficiency inhibited ferroptosis via the heme-dependent regulation of the p53/SLC7A11/GPX4 axis. The present study indicates that mPGES-2 blockage may be a promising therapeutic strategy for AKI.

Inhibition of mPGES-2 ameliorates NASH by activating NR1D1 via heme.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD), a complex metabolic syndrome, has limited therapeutic options. Microsomal prostaglandin E synthase-2 (mPGES-2) was originally discovered as a prostaglandin E 2 (PGE 2 ) synthase; however, it does not produce PGE 2 in the liver. Moreover, the role of mPGES-2 in NAFLD remains undefined. Herein, we aimed to determine the function and mechanism of mPGES-2 in liver steatosis and steatohepatitis. APPROACH AND RESULTS: To evaluate the role of mPGES-2 in NAFLD, whole-body or hepatocyte-specific mPGES-2-deficient mice fed a high-fat or methionine-choline-deficient diet were used. Compared with control mice, mPGES-2-deficient mice showed reduced hepatic lipid accumulation, along with ameliorated liver injury, inflammation, and fibrosis. Furthermore, the protective effect of mPGES-2 deficiency against NAFLD was dependent on decreased cytochrome P450 4A14 and increased acyl-CoA thioesterase 4 levels regulated by the heme receptor nuclear receptor subfamily 1 group D member 1 (NR1D1), but not PGE 2 . Heme regulated the increased NR1D1 activity mediated by mPGES-2 deficiency. Further, we confirmed the protective role of the mPGES-2 inhibitor SZ0232 in NAFLD therapy. CONCLUSION: Our study indicates the pathogenic role of mPGES-2 and outlines the mechanism in mediating NAFLD, thereby highlighting the therapeutic potential of mPGES-2 inhibition in liver steatosis and steatohepatitis.