Jiang Mingwang, Yang Zhichen, Lyu Lu, Shi Meng
Department of Nephrology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, PR China.
Department of Nephrology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China.
J Diabetes Complications. 2024 Feb;38(2):108687. doi: 10.1016/j.jdiacomp.2024.108687. Epub 2024 Jan 16.
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.
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.
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.
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.
糖尿病肾病（DN）是糖尿病的并发症，与肾内肾素-血管紧张素系统（RAS）活性密切相关。达格列净是一种钠-葡萄糖协同转运蛋白2（SGLT2）的选择性抑制剂，临床研究已证实其可改善糖尿病患者的肾脏预后，但其机制尚不清楚。本研究探讨了一种假设，即DN中肾内RAS的活性产生氧化应激以促进肾纤维化，而达格列净可中断这一过程。
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。检测生化数据、肾纤维化、氧化应激和RAS。
DN小鼠的特征为体重明显降低、血糖水平升高和肾损伤。阻断SGLT2和RAS可显著改善DN小鼠的肾功能障碍和病理损伤。与这些有益作用一致，达格列净可消除局部RAS/氧化应激以及随后的转化生长因子β（TGFβ）信号传导。
本研究阐明肾内RAS活性引发DN中的肾损伤，达格列净通过抑制血管紧张素II/TGFβ信号传导减轻肾纤维化。它为SGLT2抑制剂对DN的防治作用提供了新的见解。
