The imbalance between T helper 17 (Th17) and regulatory T (Treg) cells is an important mechanism in the pathogenesis of diabetic nephropathy (DN). Serum/glucocorticoid regulated kinase 1 (SGK1) is a serine-threonine kinase critical for stabilizing the Th17 cell phenotype. Sodium-glucose cotransporter 2 (SGLT2) is a glucose transporter that serves as a treatment target for diabetes. Our study investigated the regulatory role of SGLT2 in the development of DN. The results revealed that SGLT2 knockdown suppressed high glucose-induced excessive secretion of sodium (Na) and inflammatory cytokines in mouse renal tubular epithelial TCMK-1 cells. High Na content induced Th17 differentiation and upregulated SGK1, phosphorylated forkhead box protein O1 (p-FoxO1), and the interleukin 23 receptor (IL-23 R) in primary mouse CD4 T cells. Co-culture of CD4 T cells with the culture medium of TCMK-1 cells with insufficient SGLT2 expression significantly suppressed cell migration ability, reduced the production of pro-inflammatory cytokines, and inhibited Th17 differentiation possibly by downregulating SGK1, p-FoxO1, and IL-23 R. In addition, data demonstrated that SGLT2 knockdown markedly downregulated SGK1 in db/db mice. Insufficient SGLT2 or SGK1 expression also ameliorated the Th17/Treg imbalance, suppressed the development of DN, and regulated the expression of IL-23 R and p-FoxO1. In conclusion, this study showed that SGLT2 knockdown restored the Th17/Treg balance and suppressed DN possibly by regulating the SGK1/p-FoxO1/IL-23 R axis by altering Na content in the local environment. These findings highlight the potential use of SGLT2 and SGK1 for the management of DN.

中文翻译：

---

SGLT2 敲低可恢复 Th17/Treg 平衡，并通过 Na+ 调节 SGK1 抑制 db/db 小鼠糖尿病肾病

辅助性T细胞17（Th17）和调节性T细胞（Treg）之间的失衡是糖尿病肾病（DN）发病机制的重要机制。血清/糖皮质激素调节激酶 1 (SGK1) 是一种丝氨酸-苏氨酸激酶，对于稳定 Th17 细胞表型至关重要。钠-葡萄糖协同转运蛋白 2 (SGLT2) 是一种葡萄糖转运蛋白，可作为糖尿病的治疗靶点。我们的研究调查了 SGLT2 在 DN 发展中的调节作用。结果显示，SGLT2 敲低可抑制高葡萄糖诱导的小鼠肾小管上皮 TCMK-1 细胞钠 (Na) 和炎症细胞因子的过度分泌。高 Na 含量诱导原代小鼠 CD4 T 细胞中 Th17 分化并上调 SGK1、磷酸化叉头盒蛋白 O1 (p-FoxO1) 和白细胞介素 23 受体 (IL-23 R)。 CD4 T 细胞与 SGLT2 表达不足的 TCMK-1 细胞培养基共培养，显着抑制细胞迁移能力，减少促炎细胞因子的产生，并可能通过下调 SGK1、p-FoxO1 和 IL 抑制 Th17 分化-23 R。此外，数据表明，SGLT2 敲低可显着下调 db/db 小鼠中的 SGK1。 SGLT2 或 SGK1 表达不足还可以改善 Th17/Treg 失衡，抑制 DN 的发展，并调节 IL-23 R 和 p-FoxO1 的表达。总之，本研究表明，SGLT2 敲低可能通过改变局部环境中的 Na 含量来调节 SGK1/p-FoxO1/IL-23 R 轴，从而恢复 Th17/Treg 平衡并抑制 DN。这些发现强调了 SGLT2 和 SGK1 在 DN 治疗中的潜在用途。