Abstract
Purpose: Azilsartan, a unique angiotensin II receptor blocker (ARB) with an oxo-oxadiazole ring, exhibits antioxidant and anti-inflammatory properties, but its role in ferroptosis-mediated AKI remains unexplored. This
study investigates whether azilsartan protects against FA-induced AKI in male mice by attenuating ferroptosis,
modulating iron metabolism, and suppressing inflammatory signaling.
Methods: 42 male C57BL/6 J mice were randomized into six groups: control, FA-induced AKI, three azilsartan
doses (1, 3, 5 mg/kg), and ferrostatin-1 (Fer-1) as a positive control. Azilsartan or Fer-1 was administered for 7
days before FA injection (250 mg/kg, i.p.) and continued for 3 days post-induction. Renal function (serum urea,
creatinine), ferroptosis markers (GPX4, MDA, Nrf2, SLC7A11, HO-1), iron-handling proteins (ferritin, TfR1),
inflammatory mediators (TNF-α, NF-κB p65), and histopathology were assessed.
Results: FA-AKI caused marked renal dysfunction, elevated KIM-1, lipid peroxidation, depletion of GPX4,
downregulation of Nrf2/HO-1/SLC7A11 and TfR1, reduction of transferrin levels, and inflammatory activation.
Azilsartan improved renal function and histology in a dose-dependent manner, restored GPX4, reduced MDA,
upregulated Nrf2/HO-1/SLC7A11 and TfR1, increased ferritin levels, and suppressed TNF-α/NF-κB. High-dose
azilsartan achieved effects comparable to those of Fer-1.
Conclusion: Azilsartan confers potent protection against FA-induced AKI by activating the Nrf2/HO-1/SLC7A11/
GPX4 axis, reducing lipid peroxidation, normalizing iron metabolism, and attenuating inflammation. These
findings support azilsartan’s potential as a repurposed therapy for ferroptosis-driven renal injury.
| Has the manuscript been published | published |
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