Dexmedetomidine regulates fatty acid oxidation through the AMPK/PGC-1α/CPT1A pathway to mitigate renal ischaemia-reperfusion injury

Abstract

Objective: This study aimed to investigate whether dexmedetomidine (Dex) attenuates renal ischaemia-reperfusion injury (RIRI) by regulating fatty acid oxidation and to explore its underlying mechanisms.

Methods: A renal ischaemia-reperfusion (I/R) model was established in Sprague-Dawley rats, and a hypoxia/reoxygenation model was established using human proximal renal tubule epithelial cells. Renal function was evaluated by measuring serum creatinine and blood urea nitrogen. Oxidative stress markers malondialdehyde (MDA) and superoxide dismutase (SOD), lipid accumulation free fatty acids (FFA), triglycerides (TG) and apoptosis were assessed. Protein and mRNA expression levels of adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) and carnitine palmitoyl transferase 1 A (CPT1A) were analysed by Western blot, quantitative real-time polymerase chain reaction and immunohistochemistry. Mitochondrial ultrastructure and intracellular lipid droplets were examined by transmission electron microscopy (TEM). Molecular docking was performed to predict the interaction between Dex and AMPK, and functional validation was performed using the AMPK inhibitor Compound C.

Results: Dexmedetomidine significantly improved renal function and ameliorated histopathological damage in rats with I/R. It reduced oxidative stress (decreased MDA, increased SOD activity) and attenuated lipid accumulation (reduced FFA and TG levels)， enhancing adenosine triphosphate production in both in vivo and in vitro models. Furthermore, Dex upregulated the phosphorylation of AMPKα, the expression of PGC-1α and CPT1A at both protein and mRNA levels. The TEM revealed that Dex preserved mitochondrial integrity and reduced lipid droplet accumulation in renal tubular cells. Molecular docking indicated a strong binding affinity between Dex and AMPK, and the protective effects of Dex were reversed by Compound C.

Conclusion: Dexmedetomidine alleviates RIRI by reducing oxidative stress and promoting fatty acid oxidation through the AMPK/PGC-1α/CPT1A pathway. This study provides a potential therapeutic mechanism for the use of Dex in mitigating RIRI.

Keywords: AMPK/PGC-1α/CPT1A pathway; Dexmedetomidine; Fatty acid oxidation; Ischaemia–reperfusion injury hypoxia/reoxygenation.