Abstract: SA-PO0165
Obesity Upregulates Necroptosis in Nephrotoxic AKI
Session Information
- AKI: Mechanisms - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Mount, Peter F., Austin Health, Heidelberg, Victoria, Australia
- Katerelos, Marina, Austin Health, Heidelberg, Victoria, Australia
- Pefanis, Aspasia, Austin Health, Heidelberg, Victoria, Australia
- Ratnayake, Chathri, Austin Health, Heidelberg, Victoria, Australia
- Gleich, Kurt, Austin Health, Heidelberg, Victoria, Australia
- Lee, Mardiana, Austin Health, Heidelberg, Victoria, Australia
- Harley, Geoffrey, Austin Health, Heidelberg, Victoria, Australia
- Power, David A, The University of Melbourne Austin Clinical School, Heidelberg, Victoria, Australia
Background
Obesity disrupts renal energy metabolism and has been found to exacerbate acute kidney injury (AKI) in models of nephrotoxic injury such as folic acid nephropathy (FAN). The contribution of regulated cell death pathways—necroptosis, ferroptosis, and apoptosis—remains unclear.
Methods
Male mice were fed a high-fat diet (HFD) or control diet (CD) for six weeks to induce obesity. AKI was induced by intraperitoneal folic acid (240 µg/g), with vehicle-treated mice as controls. Kidneys were harvested 48 hours later. mRNA levels were assessed by RT-PCR; protein expression by western blot (WB) and immunohistochemistry.
Results
FAN-AKI significantly upregulated necroptosis-related mRNA markers, including RIP1, RIP3, and MLKL (P < 0.0001). Obese mice exhibited further increases in RIP3 expression at both mRNA [HFD-FAN 13.3 (3.6)-fold vs CD-FAN 9.0 (2.6)-fold, P = 0.0094] and protein levels [18.8 (2.6)-fold vs 14.8 (3.4)-fold, P = 0.0057]. MLKL phosphorylation, indicative of necroptosis activation, was significantly higher in obese FAN-AKI mice [31.9% (5.9) vs 21.0% (4.3), P = 0.0038]. While FAN-AKI altered ferroptosis markers (e.g., ACSL4 ↓, GPX4 ↑), these changes were unaffected by obesity. Apoptotic markers (BAX, BCL2 mRNA; cleaved caspase-3 protein) showed no significant differences between groups. Autophagic flux, measured by WB for LC3-II was increased by FAN, but not different with obesity.
Conclusion
Obesity amplifies necroptosis but not ferroptosis, apoptosis or autophagy, in nephrotoxic AKI. These findings highlight necroptosis as a key obesity-sensitive pathway in renal injury and a potential therapeutic target in obese patients with AKI.
Fig 1: Percentage of tubules positive for pMLKL after FAN with or without obesity.
Funding
- Government Support – Non-U.S.