ADAMTS13 ameliorates diabetic nephropathy by Nrf2/GPX4/eNOS signaling pathway

Area of Science:

• Nephrology
• Endocrinology
• Molecular Biology

Background:

• Diabetic nephropathy (DN), a complication of diabetes mellitus (DM), involves oxidative stress, ferroptosis, and mitochondrial dysfunction.
• The role of ADAMTS13 in regulating oxidative stress-mediated cell death in DN remains unclear.

Purpose of the Study:

• To investigate the protective effect and mechanism of ADAMTS13 in oxidative stress-induced cell death via the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in DN.

Main Methods:

• Collected serum from DN patients and healthy controls.
• Established DN mouse models using streptozotocin and administered recombinant human ADAMTS13 (rhADAMTS13).
• Utilized high glucose exposure on human glomerular endothelial cells and umbilical vein endothelial cells in vitro.

Main Results:

• Serum ADAMTS13 levels were decreased in DN patients.
• rhADAMTS13 activated the Nrf2/GPX4 pathway, inhibiting ROS, mitophagy, and ferroptosis, thereby reducing renal injury in DN mice.
• rhADAMTS13 enhanced eNOS phosphorylation, promoting nitric oxide (NO) production and improving endothelial dysfunction.

Conclusions:

• ADAMTS13 shows potential as a therapeutic agent for DN by modulating ferroptosis via the Nrf2/GPX4/eNOS signaling pathway.
• ADAMTS13 alleviates DN by inhibiting ferroptosis through mitophagy regulation, thereby ameliorating endothelial dysfunction.