Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, United States.
Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, United States.
Elife. 2023 May 2;12:e83353. doi: 10.7554/eLife.83353.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are anti-hyperglycemic agents that prevent glucose reabsorption in proximal tubular cells. SGLT2i improves renal outcomes in both diabetic and non-diabetic patients, indicating it may have beneficial effects beyond glycemic control. Here, we demonstrate that SGLT2i affects energy metabolism and podocyte lipotoxicity in experimental Alport syndrome (AS). In vitro, we found that the SGLT2 protein was expressed in human and mouse podocytes to a similar extent in tubular cells. Newly established immortalized podocytes from Col4a3 knockout mice (AS podocytes) accumulate lipid droplets along with increased apoptosis when compared to wild-type podocytes. Treatment with SGLT2i empagliflozin reduces lipid droplet accumulation and apoptosis in AS podocytes. Empagliflozin inhibits the utilization of glucose/pyruvate as a metabolic substrate in AS podocytes but not in AS tubular cells. In vivo, we demonstrate that empagliflozin reduces albuminuria and prolongs the survival of AS mice. Empagliflozin-treated AS mice show decreased serum blood urea nitrogen and creatinine levels in association with reduced triglyceride and cholesterol ester content in kidney cortices when compared to AS mice. Lipid accumulation in kidney cortices correlates with a decline in renal function. In summary, empagliflozin reduces podocyte lipotoxicity and improves kidney function in experimental AS in association with the energy substrates switch from glucose to fatty acids in podocytes.
钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2i）是一种抗高血糖药物，可阻止近端肾小管细胞对葡萄糖的重吸收。SGLT2i 改善了糖尿病和非糖尿病患者的肾脏结局，表明其可能具有超越血糖控制的有益作用。在这里，我们证明 SGLT2i 会影响实验性 Alport 综合征（AS）中的能量代谢和足细胞脂肪毒性。在体外，我们发现 SGLT2 蛋白在人足细胞和小鼠足细胞中的表达程度与肾小管细胞相似。与野生型足细胞相比，新建立的 Col4a3 基因敲除小鼠（AS 足细胞）的永生化足细胞积累脂滴并增加细胞凋亡。用 SGLT2i 依帕列净治疗可减少 AS 足细胞中的脂滴积累和细胞凋亡。依帕列净抑制 AS 足细胞而不是 AS 肾小管细胞对葡萄糖/丙酮酸的利用作为代谢底物。在体内，我们证明依帕列净可减少 AS 小鼠的蛋白尿并延长其生存期。与 AS 小鼠相比，依帕列净治疗的 AS 小鼠的血清血尿素氮和肌酐水平降低，肾脏皮质中的甘油三酯和胆固醇酯含量降低。肾脏皮质中的脂质积累与肾功能下降相关。总之，依帕列净可减少实验性 AS 中的足细胞脂肪毒性，并改善肾功能，这与足细胞中从葡萄糖向脂肪酸的能量底物转换有关。
