Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China.
FEBS Open Bio. 2021 May;11(5):1395-1405. doi: 10.1002/2211-5463.13147. Epub 2021 May 1.
An imbalance between T helper 17 (Th17) and T regulatory (Treg) cell subsets contributes to the pathogenesis of diabetic kidney disease (DKD). However, the underlying regulatory mechanisms that cause this imbalance are unknown. Serum/glucocorticoid-regulated kinase 1 (SGK1) has been suggested to affect Th17 polarization in a salt-dependent manner, and sodium/glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to regulate sodium-mediated transportation in the renal tubules. This study aimed to evaluate the potential benefits of dapagliflozin (Dap) on DKD, as well as its influence on shifting renal T-cell polarization and related cytokine secretion. We treated male db/db mice with Dap or voglibose (Vog) and measured blood and kidney levels of Th17 and Treg cells using flow cytometry. We found that Th17 cells were significantly increased, while Treg cells were significantly decreased in diabetic mice. Moreover, Dap suppressed the polarization of Th17/Treg cells by inhibiting SGK1 in diabetic kidneys, and this was accompanied by attenuation of albuminuria and tubulointerstitial fibrosis independent of glycemic control. Taken together, these results demonstrate that the imbalance of Th17/Treg cells plays an important role in the progression of DKD. Moreover, Dap protects against DKD by inhibiting SGK1 and reversing the T-cell imbalance.
辅助性 T 细胞 17（Th17）和调节性 T 细胞（Treg）亚群之间的失衡导致了糖尿病肾病（DKD）的发病机制。然而，导致这种失衡的潜在调节机制尚不清楚。血清/糖皮质激素调节激酶 1（SGK1）已被证明以盐依赖性的方式影响 Th17 极化，而钠/葡萄糖共转运蛋白 2 抑制剂（SGLT2i）已被证明可调节肾脏肾小管中的钠介导转运。本研究旨在评估达格列净（Dap）对 DKD 的潜在益处，以及其对肾脏 T 细胞极化和相关细胞因子分泌的影响。我们用 Dap 或伏格列波糖（Vog）治疗雄性 db/db 小鼠，并通过流式细胞术测量血液和肾脏中的 Th17 和 Treg 细胞水平。我们发现，糖尿病小鼠中 Th17 细胞明显增加，而 Treg 细胞明显减少。此外，Dap 通过抑制糖尿病肾脏中的 SGK1 抑制 Th17/Treg 细胞的极化，并且独立于血糖控制，减轻了蛋白尿和肾小管间质纤维化。综上所述，这些结果表明 Th17/Treg 细胞的失衡在 DKD 的进展中起着重要作用。此外，Dap 通过抑制 SGK1 和逆转 T 细胞失衡来保护 DKD。
