SGLT2抑制剂通过抑制CTRP1介导的糖毒性应激减轻糖尿病肾病中的肾小管衰老
SGLT2 Inhibition Attenuates Renal Tubular Senescence by Suppressing CTRP1-Mediated Glucotoxic Stress in Diabetic Kidney Disease.
摘要(中文译文)
肾小管衰老是糖尿病肾脏病（DKD）的标志性病理特征，也是疾病进展的关键驱动因素。尽管糖毒性应激被认为是肾小管老化的重要促进因素，但其上游调控机制仍不完全清楚。本研究探讨了补体C1q/肿瘤坏死因子相关蛋白1（CTRP1）在DKD相关肾小管衰老中的作用及其与SGLT2介导的葡萄糖摄取之间的机制联系。我们对人肾活检标本进行了回顾性观察性病例对照分析，并在NRK-52E细胞及高脂饮食/链脲佐菌素/单侧肾切除（HFD-STZ-UNx）大鼠模型中开展了机制实验。通过免疫组织化学和Western blotting分析了DKD患者及对照者肾皮质组织。CTRP1表达随DKD严重程度逐渐升高，并与衰老标志物p21（R = 0.498）和p16（R = 0.494）呈正相关。对CTRP1缺陷小鼠的生物信息学分析显示SGLT2一致性下调，并在NRK-52E细胞中得到实验验证，其中CTRP1过表达增加了SGLT2表达和葡萄糖摄取，尤其在高糖条件下更为明显。在HFD/STZ/UNx诱导的DKD大鼠中，达格列净（0.1 mg/kg/天）改善了代谢异常和肾功能障碍，并减轻了肾小管衰老。达格列净抑制了CTRP1-SGLT2轴的激活，减少了肾小管细胞的葡萄糖摄取，并显著降低了CTRP1与SGLT2双阳性肾小管细胞的比例。这些发现支持DKD中存在一个此前未被认识的、与葡萄糖介导的肾小管衰老相关的CTRP1-SGLT2信号轴，并为SGLT2抑制剂介导的肾脏保护提供了机制见解。
Abstract
Renal tubular senescence is a defining pathological feature of diabetic kidney disease (DKD) and a key driver of disease progression. While glucotoxic stress is recognized as a major contributor to tubular aging, the upstream regulatory mechanisms remain incompletely understood. Here, we investigated the role of C1q/TNF-related protein 1 (CTRP1) in DKD-associated tubular senescence and its mechanistic link to SGLT2-mediated glucose uptake. We conducted a retrospective observational case-control analysis of human renal biopsy specimens, complemented by mechanistic experiments in NRK-52E cells and a high-fat diet/streptozotocin/uninephrectomy (HFD-STZ-UNx) rat model. Renal cortical tissues from DKD patients and controls were analyzed via immunohistochemistry and Western blotting. CTRP1 expression increased progressively with DKD severity and was positively correlated with the senescence markers p21 (R = 0.498) and p16 (R = 0.494). Bioinformatic analysis of CTRP1-deficient mice revealed consistent SGLT2 downregulation, which was validated experimentally in NRK-52E cells, where CTRP1 overexpression increased SGLT2 expression and glucose uptake, particularly under hyperglycemic conditions. In HFD/STZ/UNx-induced DKD rats, dapagliflozin (0.1 mg/kg/day) improved metabolic abnormalities and renal dysfunction and attenuated tubular senescence. Dapagliflozin suppressed CTRP1-SGLT2 axis activation, reduced glucose uptake in renal tubular cells, and markedly decreased the proportion of CTRP1SGLT2 double-positive tubular cells. These findings support the presence of a previously unrecognized CTRP1-SGLT2 signaling axis associated with glucose-mediated tubular senescence in DKD and provide mechanistic insight into SGLT2 inhibitor-mediated renoprotection.
如何引用
AMA
Lina Gu, Buhui Liu, Lei Zhang, Jing Zhao, Weiming He, Hong Lang, et al. SGLT2 Inhibition Attenuates Renal Tubular Senescence by Suppressing CTRP1-Mediated Glucotoxic Stress in Diabetic Kidney Disease.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2026; doi:10.1096/fj.202601959R.
APA
Lina Gu, Buhui Liu, Lei Zhang, Jing Zhao, Weiming He, Hong Lang, et al (2026). SGLT2 Inhibition Attenuates Renal Tubular Senescence by Suppressing CTRP1-Mediated Glucotoxic Stress in Diabetic Kidney Disease.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.202601959R
GB/T 7714
Lina Gu, Buhui Liu, Lei Zhang, Jing Zhao, Weiming He, Hong Lang, et al. SGLT2 Inhibition Attenuates Renal Tubular Senescence by Suppressing CTRP1-Mediated Glucotoxic Stress in Diabetic Kidney Disease.[J]. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026 doi:10.1096/fj.202601959R.
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