Department of Internal Medicine, Division of Nephrology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Int J Mol Sci. 2021 Nov 17;22(22):12408. doi: 10.3390/ijms222212408.
High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transporter 2 channels presented on renal proximal tubular cells and inhibits glucose reabsorption. In addition, empagliflozin has shown renoprotective effects. However, the mechanism through which empagliflozin regulates CD36 expression and attenuates FFA-induced lipotoxicity remains unclear. Herein, we aimed to elucidate the crosstalk between empagliflozin and CD36 in FFA-induced renal injury. C57BL/6 mice fed a high-fat diet (HFD) and palmitic acid-treated HK-2 renal tubular cells were used for in vivo and in vitro assessments. Empagliflozin attenuated HFD-induced body weight gain, insulin resistance, and inflammation in mice. In HFD-fed mice, CD36 was upregulated in the tubular area of the kidney, whereas empagliflozin attenuated CD36 expression. Furthermore, empagliflozin downregulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment with a PPARγ inhibitor (GW9662) did not further decrease PPARγ expression, whereas a PPARγ antagonist reversed this effect; this suggested that empagliflozin may, at least partly, decrease CD36 by modulating PPARγ. In conclusion, empagliflozin can ameliorate FFA-induced renal tubular injury via the PPARγ/CD36 pathway.
高血清游离脂肪酸（FFAs）水平可能导致肥胖相关性肾病。CD36 是 B 类清道夫受体，是介导肾近端小管细胞摄取 FFA 的主要受体。恩格列净是一种新型抗糖尿病药物，是肾近端小管细胞上钠-葡萄糖协同转运蛋白 2 通道的特异性抑制剂，可抑制葡萄糖重吸收。此外，恩格列净还具有肾脏保护作用。然而，恩格列净调节 CD36 表达并减轻 FFA 诱导的脂毒性的确切机制尚不清楚。本研究旨在阐明恩格列净与 FFA 诱导的肾损伤中 CD36 之间的相互作用。采用高脂肪饮食（HFD）喂养 C57BL/6 小鼠和棕榈酸处理的 HK-2 肾小管细胞进行体内和体外评估。恩格列净可减轻 HFD 诱导的小鼠体重增加、胰岛素抵抗和炎症。在 HFD 喂养的小鼠中，肾脏小管区域 CD36 上调，而恩格列净可减轻 CD36 表达。此外，恩格列净下调过氧化物酶体增殖物激活受体（PPAR）-γ的表达。用 PPARγ 抑制剂（GW9662）处理不会进一步降低 PPARγ 的表达，而 PPARγ 拮抗剂则逆转了这种作用；这表明恩格列净至少部分通过调节 PPARγ 来降低 CD36。总之，恩格列净可通过 PPARγ/CD36 途径改善 FFA 诱导的肾小管损伤。
