RESUMEN
Previous research has demonstrated that Dexmedetomidine (DEX), an α2 adrenergic agonist commonly used for its sedative and analgesic properties, can attenuate lipopolysaccharide (LPS)-induced acute kidney injury (AKI). This study explores the possibility that DEX's protective effects in LPS-induced AKI are mediated through the inhibition of ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, and the activation of the antioxidant response through the Keap1/Nrf2/HO-1 signaling pathway. We induced AKI in 42 mice using LPS and divided them into six groups: saline control, LPS, LPS + DEX, LPS + Ferrostatin-1 (LPS + Fer-1; a ferroptosis inhibitor), LPS + DEX with α2-receptor antagonist Altipamizole (LPS + DEX + ATI), and LPS + DEX with Nrf2 inhibitor ML385 (LPS + DEX + ML385). After 24 h, we analyzed blood and kidney tissues. LPS exposure resulted in AKI, with increased serum creatinine, BUN, and cystatin C, and tubular damage, which DEX and Fer-1 ameliorated. However, Altipamizole and ML385 negated these improvements. The LPS group exhibited elevated oxidative stress markers and mitochondrial damage, reduced by DEX and Fer-1, but not when α2-adrenergic or Nrf2 pathways were blocked. Nrf2 and HO-1 expression declined in the LPS group, rebounded with LPS + DEX and LPS + Fer-1, and fell again with inhibitors; inversely, Keap1 expression varied. Our results demonstrate that DEX may protect against LPS-induced AKI, at least partially by regulating ferroptosis and the α2-adrenergic receptor/Keap1/Nrf2/HO-1 pathway, suggesting a potential therapeutic role for DEX in AKI management by modulating cell death and antioxidant defenses.
RESUMEN
BACKGROUND: Dexmedetomidine (DEX) reportedly protects against ischemia-reperfusion (I/R) injury and associated damage to the kidneys, but the underlying mechanisms have yet to be established. METHODS: Unilateral nephrectomy was performed in Wistar rats, and the remaining kidney was clamped for 1 h prior to reperfusion to establish an experimental model system. These animals were then randomized into Sham, DEX + Sham, DEX + I/R, ATI (Altepamizole, α2-adrenergic receptor inhibitor) + DEX + I/R, and 3-MA (3-methyladenine, autophagy inhibitor) + DEX + I/R groups. Serum renal function biomarkers, acute kidney injury (AKI) histopathological scores, serum inflammatory factors, redox biomarkers, markers of autophagic flux, and autophagosome numbers were assessed. Levels of proteins related to the autophagic pathway, including mTOR and AMPK, were also analyzed. RESULTS: Serum creatinine and urea nitrogen levels in the I/R group were significantly elevated over those in sham control rats, as were AKI scores, serum inflammatory cytokine concentrations (IL-6, IL-1ß, and TNF-α), and serum levels of the oxidative stress biomarker malondialdehyde (MDA). All of these parameters were significantly reduced in the DEX + I/R group relative to I/R model rats. I/R group rats also exhibited significant decreases in renal levels of autophagic flux-related biomarkers and autophagosome numbers relative to sham controls, while DEX administration partially restored normal autophagic flux in these rats. Acute I/R also suppress the expression of AMPK in the kidney while increasing mTOR expression, and DEX reversed these effects. The beneficial impact of DEX on I/R-associated AKI was ablated by ATI or 3-MA administration. CONCLUSIONS: These analyses provide strong evidence for the ability of DEX to protect against I/R-associated AKI via the α2-AR/AMPK/mTOR pathway-mediated enhancement of autophagic activity.
