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作者

Dan Wang, Furong Zhu, Miao Miao Shao, Huimei Zang, Xue Xia

作者单位

Jianmin Road, Qingdao, 266200, China. ³ The People's Hospital of Sishui, Quantong Road, Sishui, 273200, China. ⁴ Center for Gene and Immunotherapy, The Second Hospital, Cheeloo College of Medicine, Shandong University, No.44 Wenhua West Road, Jinan, 250033, China. ⁵ Multidisciplinary Innovation Center for Nephrology of the Second Hospital, Cheeloo College of Medicine, Shandong University, No.44 Wenhua West Road, Jinan, 250033, China. ⁶ Department of General Medicine, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Jinan, 250013, China. xiaxue@sdfmu-edu.cn. Affiliations ¹ Department of Nephrology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Jinan, 250013, China. ² Department of Hemodialysis, People's Hospital of Jimo District, No

刊名

Naunyn-Schmiedeberg's archives of pharmacology

年份

2025

ISSN

1432-1912

关键词

Diabetic Nephropathy Ferroptosis Glucotoxicity HMGB1 Irisin Nrf2.

摘要

Diabetic nephropathy is a global health threat with limited therapeutic interventions. Irisin, a myokine derived from FNDC5, has been implicated in glucose homeostasis and anti-diabetic effects; however, its precise mechanistic role in glucose metabolism regulation remains elusive. This study elucidates the specific role of Irisin in mitigating diabetic renal tubular epithelial injury, with a focus on its regulatory mechanisms under glucotoxic conditions. Utilizing streptozotocin -induced type ...更多

Diabetic nephropathy is a global health threat with limited therapeutic interventions. Irisin, a myokine derived from FNDC5, has been implicated in glucose homeostasis and anti-diabetic effects; however, its precise mechanistic role in glucose metabolism regulation remains elusive. This study elucidates the specific role of Irisin in mitigating diabetic renal tubular epithelial injury, with a focus on its regulatory mechanisms under glucotoxic conditions. Utilizing streptozotocin -induced type 1 diabetes mouse models and high glucose -stimulated HK-2 cells, we demonstrated that STZ-induced DN mice exhibited renal dysfunction, oxidative stress, and iron accumulation. Sustained HG exposure downregulated glutathione peroxidase 4 and xCT while upregulating Ptgs2 and FPN1, indicative of Ferroptosis initiation. Irisin treatment significantly attenuated these pathological changes and ameliorated renal tubular epithelial injury. Mechanistically, this protective effect was mediated through the activation of high-mobility group box-1 , a damage-associated regulator, as observed in both in vivo and in vitro studies. Furthermore, we identified the nuclear translocation of Nrf2 and its downstream target GPX4 in vitro. Specific interference with Nrf2, through both knockdown and overexpression experiments under HG conditions, further demonstrated Irisin's regulatory role on HMGB1. This was validated by assessing tubular epithelial cell viability, alongside cellular levels of malondialdehyde , glutathione , superoxide dismutase , and Fe content. Notably, Nrf2 co-transfection nullified the protective effects of Irisin, exacerbating Ferroptosis markers. Collectively, our findings reveal that Irisin protects against glucotoxicity-induced renal injury by inhibiting tubular epithelial Ferroptosis via the HMGB1/Nrf2/GPX4 axis, thereby proposing a novel therapeutic target for DN.收起

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