NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.
Front Immunol. 2022 Dec 1;13:993869. doi: 10.3389/fimmu.2022.993869. eCollection 2022.
Idiopathic membranous nephropathy is the main cause of chronic kidney disease (CKD). Studies have shown sodium-glucose co-transporter 2 (SGLT2) inhibitors significantly delay renal outcomes in patients with CKD, but the exact mechanism remains unknown. In this study, we investigated the mechanism by which the SGLT2 inhibitor canagliflozin attenuates podocyte injury by reversing the imbalance in Helper T cell 1 (Th1)/Helper T cell 2 (Th2) in peripheral blood of rats with membranous nephropathy (MN). MN rats were gavaged with canagliflozin (10 mg/kg/d) and losartan (10 mg/kg/d), respectively, for eight weeks. Compared with the MN group, the urinary ratio of total protein and the creatinine levels of the canagliflozin group decreased significantly. Canagliflozin improved the glomerulus pathological damage, increased the expression levels of podocyte marker proteins. The protective effect of canagliflozin on kidneys was more obvious than that of losartan. Treatment with canagliflozin increased the proportion of Th1 cells by 2.3 times, decreased the proportion of Th2 cells by 68.5%, and significantly restrained the synthesis of immunoglobulin G1 in B-cells and glomerulus subepithelial immune complex deposition. Co-culture of B-cells derived from MN rats with podocytes triggered the activation of phosphorylation of mTOR and ULK1 of podocytes, inhibited podocyte autophagy and resulted in podocyte injury. B-cells derived from canagliflozin treatment rats reversed these effects above. In conclusion, canagliflozin exerts a protective effect on kidneys by reversing the imbalance in Th1/Th2 cells in MN rats and restoring the autophagy of podocytes inhibited by the abnormal immunoglobulin G secretion from B-cells.
特发性膜性肾病是慢性肾脏病（CKD）的主要病因。研究表明，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂可显著延缓 CKD 患者的肾脏结局，但确切机制尚不清楚。在这项研究中，我们通过逆转膜性肾病（MN）大鼠外周血辅助性 T 细胞 1（Th1）/辅助性 T 细胞 2（Th2）失衡，研究 SGLT2 抑制剂坎格列净减轻足细胞损伤的机制。MN 大鼠分别灌胃坎格列净（10mg/kg/d）和氯沙坦（10mg/kg/d）8 周。与 MN 组相比，坎格列净组的尿总蛋白比和肌酐水平明显降低。坎格列净改善了肾小球的病理损伤，增加了足细胞标记蛋白的表达水平。坎格列净对肾脏的保护作用比氯沙坦更明显。坎格列净治疗使 Th1 细胞的比例增加了 2.3 倍，Th2 细胞的比例减少了 68.5%，显著抑制了 B 细胞免疫球蛋白 G1 的合成和肾小球基底膜下免疫复合物的沉积。MN 大鼠来源的 B 细胞与足细胞共培养可触发足细胞中 mTOR 和 ULK1 的磷酸化激活，抑制足细胞自噬，导致足细胞损伤。来自坎格列净治疗大鼠的 B 细胞逆转了上述这些作用。总之，坎格列净通过逆转 MN 大鼠 Th1/Th2 细胞失衡，并恢复由 B 细胞异常分泌免疫球蛋白抑制的足细胞自噬，对肾脏发挥保护作用。
