Underlying metabolic syndrome exacerbates <i>Vibrio vulnificus-</i>induced acute kidney injury via systemic Th17/Treg dysregulation

Climate change has led to a rise in <i>Vibrio vulnificus</i> infections, while the global obesity epidemic has increased susceptibility to severe bacterial infections. Obesity and high-fat diet (HFD) consumption promote systemic inflammation and immune dysregulation, which may exacerbate sepsis and its complications, including acute kidney injury (AKI). This study investigates the mechanistic role of HFD-induced metabolic dysfunction in <i>V. vulnificus</i> sepsis-associated AKI. Adult C57BL/6J mice were placed on a standard CHOW diet or a 60% kcal HFD for 6 wk before infection. <i>V. vulnificus</i> infection was induced via intragastric administration by oral gavage of 10⁸ colony-forming units of <i>V. vulnificus</i> suspended in PBS. Kidney function was assessed, and kidney tissues were analyzed for markers of inflammation, oxidative stress, and necrosis. Systemic Th17/Treg ratios were determined. In vitro, renal proximal tubular epithelial cells were treated with leptin and IL-17A with/without an IL-17 receptor antagonist to confirm the role of IL-17 signaling in renal epithelial cell pathology. A proinflammatory Th17/Treg imbalance, along with a marked increase in renal TLR4 activation, inflammation, and necrosis, was observed in the HFD + <i>Vibrio vulnificus</i> infection group. In vitro studies confirmed that IL-17 and leptin synergistically activate the NF-κB pathway, promoting inflammatory cytokine release. These findings indicate that HFD-induced metabolic stress exacerbates <i>V. vulnificus</i> sepsis-associated AKI. The interplay between IL-17 signaling and leptin may further amplify renal injury, underscoring the need for targeted interventions. Strategies to modulate IL-17 signaling and metabolic inflammation may offer novel therapeutic approaches to reduce AKI severity in obese individuals with bacterial sepsis.<b>NEW & NOTEWORTHY</b> This study reveals that high-fat diet (HFD)-induced metabolic dysfunction exacerbates <i>Vibrio vulnificus</i> sepsis-associated acute kidney injury (AKI) via TLR4-driven inflammation, oxidative stress, and systemic Th17/Treg imbalance. Novel in vitro findings show that IL-17 and leptin synergistically activate NF-κB signaling in renal epithelial cells, amplifying inflammation, which is mitigated by IL-17 receptor blockade. These results highlight IL-17 signaling as a potential therapeutic target for reducing AKI severity in obese individuals with bacterial sepsis.