Alliin mitigates the acute kidney injury by suppressing ferroptosis via regulating the Nrf2/GPX4 axis.

Abstract

Acute kidney injury (AKI) is a clinical syndrome that is characterized by a sudden loss of kidney function, leading to severe metabolic disorders, multiple organ failure, and even death. Recent studies have strengthened the evidence for ferroptosis in AKI development. Alliin, a sulfur-containing amino acid with multiple pharmacological functions, was claimed with promising antioxidant and anti-inflammation effects in protecting organ damages. Herein, Alliin's potential in AKI treatment was investigated by exploring its impact on ferroptosis, providing a new strategy for clinical AKI treatments. Cecal ligation and puncture (CLP) modeling was performed on rats, followed by treated with 7.5 and 15mg/kg/day of alliin for 6days. A declined survival rate, severe renal pathological changes, renal dysfunction, and enhanced inflammatory state were observed in CLP-treated rats, which were remarkably alleviated by alliin. Moreover, increased MDA levels, declined SOD activity, and downregulated Nrf2, GPX4, and xCT in CLP-treated rats were notably reversed by alliin. To explore potential mechanisms of alliin, NRK-52E cells were stimulated with 1μg/mL LPS for 24h, followed by culturing with 30 and 100μM of alliin for 24h. Reduced cell viability, enhanced apoptosis, increased ROS production, boosted MDA level, and declined SOD activity were observed in LPS-stimulated NRK-52E cells, accompanied by downregulated Nrf2, GPX4, and xCT, which were strikingly ameliorated by alliin. Additionally, the influence of alliin on cell viability, oxidative stress (OS), and ferroptosis in LPS-stimulated NRK-52E cells were markedly abolished by silencing Nrf2. Collectively, alliin mitigated AKI by suppressing ferroptosis via regulating the Nrf2/GPX4 axis.