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.
摘要：
糖尿病肾病(DKD)是糖尿病最常见的并发症之一。临床上没有特定的药物。我们先前已经证明，抑制微粒体前列腺素E合酶2（mPGES-2）通过增强β细胞功能和促进胰岛素产生来减轻2型糖尿病。然而,mPGES-2是否参与DKD尚不清楚.这里,我们旨在分析mPGES-2表达增强与肾脂代谢稳态受损以及随后的肾损害之间的关联.值得注意的是,mPGES-2的整体敲除或药物阻断减轻了糖尿病足细胞损伤和肾小管间质纤维化，从而改善脂质积累和脂毒性。这些发现在足细胞或小管特异性mPGES-2缺陷小鼠中得到进一步证实。机械上,mPGES-2和Rev-Erbα竞争血红素结合以调节糖尿病肾脏中脂肪酸结合蛋白5的表达和脂质代谢。我们的发现提示了通过mPGES-2抑制治疗DKD的潜在策略。
