Magnesium Sulfate Alleviates Sepsis-Associated Acute Kidney Injury by Reducing Inflammation, Oxidative Stress, and...

Acute kidney injury is one of the most common complications of sepsis, characterized by high incidence and mortality. There is an urgent need for novel therapeutic strategies to improve the outcomes for patients with sepsis-associated acute kidney injury (SA-AKI). Our previous study demonstrated that magnesium sulfate (MgSO₄) exerts renoprotective effects in septic patients. This study aimed to explore the underlying protective mechanisms of MgSO₄ in SA-AKI. C57BL/6J mice were randomly assigned to five groups: the control group, the lipopolysaccharide (LPS, 10 mg/kg) group, and three MgSO₄ treatment groups receiving low, medium, and high dose (50, 100, 150 mg/kg, respectively). Renal function, histopathology, inflammatory markers, oxidative stress, mitochondrial function, and apoptosis were assessed. The results demonstrated that MgSO₄ significantly improved renal function, reducing kidney injury following LPS challenge. MgSO₄ also suppressed systemic and renal inflammation, as evidenced by decreased TNF-α, IL-6, or IL-1β levels in HK-2 cells, serum, and kidney tissues. Mechanistically, MgSO₄ alleviated oxidative stress and mitochondrial dysfunction in HK-2 cells, reducing mitochondrial Ca²⁺ loading and ROS production while restoring ATP content, antioxidant capacity, and mitochondrial membrane potential. Transcriptomic profiling of renal tissue identified inflammation and cell death related pathways as major LPS-responsive signatures and suggested NF-κB signaling as a potential MgSO₄-modulated axis. MgSO₄ inhibited intrinsic apoptosis both in vitro and in vivo, reflected by a reduced Bax/Bcl-2 ratio, decreased caspase-9 activation and cleaved caspase-3 signals, and fewer TUNEL-positive cells. Consistently, immunohistochemistry and immunoblotting confirmed that MgSO₄ inhibited renal NF-κB activation, reflected by reduced phosphorylation of p65 (p-p65). Collectively, these findings suggest that MgSO₄ mitigates SA-AKI by dampening inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis, at least in part through inhibition of NF-κB signaling, supporting its therapeutic potential for SA-AKI.