MicroRNA-483-5p accentuates cisplatin-induced acute kidney injury by targeting GPX3

Area of Science:

• Nephrology
• Molecular Biology
• Genetics

Background:

• Cisplatin (cis-diamminedichloroplatinum II) is a widely used chemotherapy agent with known nephrotoxicity, but its precise molecular mechanisms remain unclear.
• MicroRNA-483 (miR-483) has been implicated in various diseases, yet its role in kidney injury, specifically cisplatin-induced acute kidney injury (AKI), is not established.

Purpose of the Study:

• To investigate the pathogenic role and molecular mechanism of miR-483-5p in cisplatin-induced AKI.
• To identify the renal targets of miR-483-5p and its contribution to AKI pathogenesis.

Main Methods:

• Utilized a cisplatin-induced mouse model, clinical serum samples from patients undergoing cisplatin therapy, and an in vitro NRK-52E cell line.
• Employed stereotactic renal injection of lentiviruses for miR-483-5p overexpression in mouse kidneys and generated conditional miR-483-overexpressing transgenic mice.
• Investigated the direct targeting of miR-483-5p using molecular assays and assessed its impact on oxidative stress, apoptosis, and autophagy.

Main Results:

• miR-483-5p was significantly upregulated by cisplatin in vivo, in patient serum, and in vitro.
• Overexpression of miR-483-5p exacerbated cisplatin-induced AKI, characterized by increased oxidative stress, apoptosis, and inhibited autophagy in tubular cells.
• miR-483-5p directly targets GPX3; its overexpression rescued cisplatin-induced AKI by reducing oxidative stress and apoptosis, but not autophagy.

Conclusions:

• Cisplatin upregulates miR-483-5p, which exacerbates cisplatin-induced AKI through the negative regulation of GPX3, leading to increased oxidative stress and tubular cell apoptosis.
• miR-483-5p plays a significant pathogenic role in cisplatin-induced AKI.
• miR-483-5p represents a potential novel target for the diagnosis and treatment of AKI.