Mitochondrial Quality Control Systems in Septic AKI: Molecular Mechanisms and Therapeutic Implications.

Despite significant advancements in medical treatments, the creation of a successful treatment strategy for acute kidney injury (AKI) remains a pressing concern. Given the well-documented clinical benefits of canagliflozin in renal protection, our research focused on exploring the possible therapeutic benefits of canagliflozin in treating AKI, with a focus on its underlying mechanisms of action. To induce AKI, we utilized lipopolysaccharide (LPS) in the presence of canagliflozin, allowing us to assess the drug's effects on kidney function and structure. Our results indicate that canagliflozin lowered blood urea nitrogen and serum creatinine concentrations while enhancing tubular architecture in rodents with LPS-triggered septic AKI. It additionally diminished inflammation, oxidative damage, and tubular cell apoptosis. , canagliflozin maintained mitochondrial functionality in LPS-exposed HK-2 cells by stabilizing membrane potential, reducing ROS generation, and normalizing respiratory chain activity. Its benefits were facilitated through the AMPKα1/PGC1α/NRF1 axis, promoting mitochondrial regeneration. Importantly, blocking this pathway or employing AMPKα1-deficient animals negated canagliflozin's protective effects, highlighting the essential role of AMPKα1 in its kidney-protective mechanisms. Our investigation implies that canagliflozin might represent a viable treatment strategy for septic AKI, operating through the stimulation of the AMPKα1/PGC1α/NRF1 axis to preserve kidney performance and structural integrity. These findings warrant further investigation into the clinical potential of canagliflozin in this context.