Objective: Sepsis-associated acute kidney injury (AKI) involves interconnected disturbances in renal redox balance, inflammatory signaling, and inflammatory cell death, including pyroptosis. While oxidative stress is a known contributor, the roles of the NLRP3 inflammasome and the pro-inflammatory cytokine interleukin 17 (IL-17) in this pathology are of growing interest. Here, we examined whether diosgenin could counteract renal injury produced by systemic lipopolysaccharide (LPS) exposure, with particular emphasis on inflammatory and pyroptotic signaling.
Materials and Methods: Thirty-two male C57BL/6 mice were randomly divided into four groups (n=8 per group): Control, Control + Diosgenin (40 mg/kg), LPS (10 mg/kg), and LPS + Diosgenin (40 mg/kg). Diosgenin was administered via oral gavage 1 hr prior to a single dose of LPS injection (i.p.). After 24 hr, renal function was assessed in terms of serum creatinine, blood urea nitrogen (BUN), and cystatin C levels. Oxidative stress markers (malondialdehyde (MDA), superoxide dismutase (SOD), and nitrite) were also measured. In addition, renal levels of NLRP3, caspase-1, and IL-17 were determined. Finally, myeloperoxidase (MPO) activity and mitochondrial membrane potential (MMP) were assessed.
Results: Pretreatment with diosgenin mitigated the functional renal impairment induced by LPS, as reflected by lower levels of creatinine, BUN, and cystatin C and reduced oxidative stress (lower MDA and higher SOD). It also suppressed key inflammatory mediator IL-17 and pyroptotic NLRP3/caspase-1 pathway, MPO activity, and mitochondrial dysfunction.
Conclusion: These findings indicate that diosgenin confers renoprotection against LPS-induced AKI that is associated with attenuation of oxidative stress, IL-17-related inflammatory responses, NLRP3/caspase-1 signaling, and preservation of MMP. Collectively, these results support the potential of diosgenin as a promising multi-target protective agent in sepsis-associated AKI.