Pharmacological administration of anti-oxidative APP-103 protects the acute kidney injury by regulating the mitochondrial function and ferroptosis

Background: Acute Kidney Injury (AKI) frequently occurs in hospitalized patients and predisposes them to developing chronic kidney disease (CKD). AKI is characterized by rapid decline in kidney function associated with raises in blood creatinine, BUN, and damage to kidney tissue, including major histological changes such as acute tubular damage, mitochondrial dysfunction, and inflammation induced by excess reactive oxygen species (ROS), which all play a crucial role in AKI. Although small molecule antioxidants are known to be beneficial in alleviating AKI, low bioavailability and side-effects of ROS-scavenging compounds tremendously limit their clinical use. Therefore, our current study tests the hypothesis that the pharmacological inhibition of ROS by nanoparticles (NP) containing APP-103, a novel copolyoxalate molecule that scavenges ROS and releases vanillyl alcohol, will improve outcomes in a cisplatin induced mouse model of AKI. Methods: 16-week old C57BL/6J mice were studied in cisplatin induced AKI. Mice in the treatment group were treated with nanoparticles (3.0 mg/kg) via intraperitoneal administration for 2-days prior to cisplatin injection and followed by another 3-days of NP treatment. 72-hours after, plasma samples were collected to measure creatinine and BUN, and kidneys excised for biochemical and histological evaluation. Gene and protein expression levels were then analyzed by qRT-PCR and westernblot. Results: Plasma creatinine and BUN levels were higher in mice administered cisplatin (CP) alone compared to vehicle, whereas treatment with nanoparticles (CP + NP) reduced their levels significantly. Westernblot analysis indicated that kidney injury molecule (KIM1) increased in cisplatin group and decreased significantly in the kidney of CP+NP mice group. Interestingly, we found upregulation of ferroptosis and lipid peroxidation marker 4-HNE, and downregulation of anti-ferroptosis marker Gpx4 in the kidneys of mice with AKI and treatment with nanoparticles prevented these changes. Westernblot analysis determined that the mitochondrial complex I, II and IV expression levels were reduced significantly in the kidneys of CP mice and their reduction were prevented in mice administered with nanoparticles. The proinflammatory cytokine MCP1 and profibrotic markers Col3a1, Timp1 and fibronectin levels were markedly increased in CP mice, and NP treatment significantly reduced their expression levels. Conclusion: Our results show that the administration of APP-103 nanoparticles exhibits a renal protective role by inhibiting mitochondrial damage and ferroptosis, thereby preventing renal tubular damage under acute kidney injury. This work was supported by NIH (NIDDK) award numbers R01DK127830 (ML) and R01 DK139676 (ML). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.