Aims

Diabetic nephropathy (DN) complicates diabetes Mellitus and intimately relates to intrarenal renin–angiotensin system (RAS) activity. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), has been validated to improve renal outcomes in diabetic patients from clinical research by elusive mechanisms. This study explored the presumption that the eagerness activity of intrarenal RAS in DN generated oxidative stress to promote renal fibrosis, and the process can be interrupted by dapagliflozin.

Methods

A streptozotocin-induced DN model was established in male C57BL/6J mice. Mice were treated with dapagliflozin or losartan for 14 weeks. Biochemical data, renal fibrosis, oxidative stress, and RAS were measured.

Results

DN mice were characterized by overtly low body weight, high levels of blood glucose, and renal injury. Interrupting SGLT2 and RAS significantly improved renal dysfunction and pathological lesions in DN mice. Consistent with these favorable effects, dapagliflozin revoked the local RAS/oxidative stress and the succeeding transforming growth factor beta (TGFβ) signaling.

Conclusions

This research clarifies that intrarenal RAS activity triggers renal injury in DN, and dapagliflozin attenuates renal fibrosis by suppressing Angiotensin II/TGFβ signaling. It unravels a novel insight into the role of prevention and treatment of SGLT2 inhibitors to DN.

中文翻译：

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达格列净通过抑制糖尿病小鼠的血管紧张素 II/TGFβ 信号传导来减轻肾纤维化

目标

糖尿病肾病（DN）使糖尿病复杂化，并与肾内肾素-血管紧张素系统（RAS）活性密切相关。Dapagliflozin是一种钠-葡萄糖协同转运蛋白 2 (SGLT2) 的选择性抑制剂，临床研究已通过难以捉摸的机制验证其可改善糖尿病患者的肾脏结局。本研究探讨了以下假设：DN 肾内 RAS 的急切活性产生氧化应激，促进肾纤维化，而达格列净可以中断这一过程。

方法

在雄性 C57BL/6J 小鼠中建立链脲佐菌素诱导的 DN 模型。小鼠接受达格列净或氯沙坦治疗 14 周。测量生化数据、肾纤维化、氧化应激和 RAS。

结果

DN 小鼠的特点是体重过低、血糖水平高和肾损伤。干扰 SGLT2 和 RAS 可显着改善 DN 小鼠的肾功能障碍和病理病变。与这些有利的作用一致，达格列净消除了局部 RAS/氧化应激和随后的转化生长因子 β (TGFβ) 信号传导。

结论

这项研究阐明，肾内 RAS 活性会引发 DN 肾损伤，达格列净通过抑制血管紧张素 II/TGFβ 信号传导来减轻肾纤维化。它揭示了 SGLT2 抑制剂预防和治疗 DN 作用的新见解。