Table_3_Empagliflozin Attenuates Obesity-Related Kidney Dysfunction and NLRP3 Inflammasome Activity Through the HO-1–Adiponectin Axis.docx

Empagliflozin (EMPA) is a novel sodium-glucose cotransporter 2 inhibitor (SGLT2i) that produces protective cardiovascular-renal outcomes in patients with diabetes. However, the effects of EMPA on obesity-related kidney disease have not been determined. The heme oxygenase-1 (HO-1)–adiponectin axis is an essential antioxidant system with anti-apoptotic and anti-inflammatory properties. This study explored whether EMPA improves obesity-related kidney disease through regulation of the renal HO-1-mediated adiponectin axis. C57BL/6J mice were assigned to control, high-fat diet (HFD) groups, and EMPA (10 mg/kg) groups. HFD mice showed metabolic abnormality and renal injury, including increased urinary albumin excretion, morphologic changes, and lipid accumulation. EMPA treatment improved metabolic disorders and attenuated lipotoxicity-induced renal injury. Furthermore, EMPA treatment ameliorated renal NLRP3 inflammasome activity and upregulated the HO-1–adiponectin axis. Our findings indicate that EMPA improves obesity-related kidney disease through reduction of NLRP3 inflammasome activity and upregulation of the HO-1–adiponectin axis, suggesting a novel mechanism for SGLT2i-mediated renal protection in obesity.

恩格列净（Empagliflozin, EMPA）是一种新型钠-葡萄糖协同转运蛋白2抑制剂（sodium-glucose cotransporter 2 inhibitor, SGLT2i），可在糖尿病患者中发挥心血管与肾脏保护作用。然而，恩格列净对肥胖相关性肾病的作用尚未明确。血红素氧合酶-1（heme oxygenase-1, HO-1）-脂联素轴是一类兼具抗氧化、抗凋亡及抗炎特性的关键抗氧化系统。本研究旨在探讨恩格列净是否通过调控肾脏HO-1介导的脂联素轴改善肥胖相关性肾病。实验将C57BL/6J小鼠分为对照组、高脂饮食（high-fat diet, HFD）组及恩格列净（10 mg/kg）干预组。结果显示，高脂饮食小鼠出现代谢异常与肾损伤，具体表现为尿白蛋白排泄增加、肾脏形态学改变及脂质蓄积。恩格列净干预可改善小鼠代谢紊乱，减轻脂毒性诱导的肾损伤。进一步研究发现，恩格列净干预可抑制肾脏NLRP3炎症小体活性，并上调HO-1-脂联素轴的表达。本研究结果表明，恩格列净可通过降低NLRP3炎症小体活性并上调HO-1-脂联素轴改善肥胖相关性肾病，提示SGLT2i介导的肥胖相关肾脏保护作用存在全新机制。