ADAMTS13 ameliorates diabetic nephropathy by Nrf2/GPX4/eNOS signaling pathway.
Wang Honghong, Guo Jie, Wang Qingqing, Cai Fanghao, Jiang Shan, Fei Lingyan, Zhang Gensheng, Yu Guizhen, Li Bingjue, Zhou Jingyi, Li Zheng, Han Fei, Lai En Yin, Zhou Suhan
Abstract
Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus (DM). Accumulated reactive oxygen species (ROS) and oxidative stress-induced ferroptosis and mitochondrial dysfunction play a critical role in the development of DN. The aim of this research was to investigate the protective role and mechanism of ADAMTS13 in regulating oxidative stress-mediated cell death via nuclear factor erythroid 2-related factor 2 (Nrf2) in DN. In this study, DN patients with renal biopsy-confirmed and healthy controls were collected. In vivo, DN mice models were established by intraperitoneal injection of streptozotocin, followed by tail vein administration of recombinant human ADAMTS13 (rhADAMTS13). In vitro, human glomerular endothelial cells and human umbilical vein endothelial cells were exposed to high glucose. The results demonstrated that serum ADAMTS13 was decreased in DN patients. rhADAMTS13 inhibited ROS generation by activating the Nrf2/GPX4 signaling pathway, thereby inhibiting mitophagy and ferroptosis, ultimately ameliorating renal injury in DN mice. Meanwhile, endothelial nitric oxide synthase (eNOS) phosphorylation was enhanced, which promoted the production of endogenous NO, and then improved vascular endothelial dysfunction. In vitro, rhADAMTS13 inhibited the production of ROS in both cytoplasm and mitochondria, while concurrently reducing the release of NO. Our findings suggest that ADAMTS13 may be a potential therapeutic agent for DN through Nrf2/GPX4/eNOS signaling pathway. ADAMTS13 may alleviate DN by inhibiting modulating ferroptosis through the regulation of mitophagy, thereby ameliorating endothelial dysfunction.
Key Findings
- Serum ADAMTS13 levels are decreased in diabetic nephropathy (DN) patients.
- Recombinant human ADAMTS13 (rhADAMTS13) activates the Nrf2/GPX4 signaling pathway, reducing ROS generation and inhibiting mitophagy and ferroptosis.
- rhADAMTS13 enhances eNOS phosphorylation, increasing endogenous NO production and improving vascular endothelial dysfunction in DN models.
Clinical Significance
ADAMTS13 shows potential as a therapeutic agent for diabetic nephropathy by modulating ferroptosis and oxidative stress through the Nrf2/GPX4/eNOS signaling pathway, thereby protecting renal function and vascular health.
Citation
Wang Honghong, Guo Jie, Wang Qingqinget al.. ADAMTS13 ameliorates diabetic nephropathy by Nrf2/GPX4/eNOS signaling pathway. Renal failure. 2026-Dec.