Acute kidney injury-induced acute lung injury (AKI-ALI) is a severe clinical syndrome characterized by systemic inflammation, oxidative stress, and immune cell activation. Vascular non-inflammatory molecule-1 (Vanin-1, VNN1), a pantetheinase enzyme involved in oxidative stress and inflammation, has been implicated in various inflammatory diseases. However, its role in AKI-ALI and its therapeutic potential remain unclear. An AKI-ALI model was established via bilateral kidney ischemia-reperfusion (KIR) in mice. VNN1-/- mice and pharmacological inhibition of Vanin-1 with RR6 were used to evaluate its role in AKI-ALI. Lung injury, oxidative stress, and inflammation were assessed using histological analysis, biochemical assays, and proteomic profiling. Neutrophil extracellular traps (NETs) formation was evaluated in vitro using immunofluorescence and ELISA. KIR-induced AKI resulted in severe lung injury, characterized by impaired oxygenation, increased broncho-alveolar lavage fluid protein leakage, and elevated inflammatory cytokines. Vanin-1 knockout significantly alleviated lung injury, reduced oxidative stress, and suppressed inflammation, without affecting renal injury. Proteomic and bioinformatics analyses revealed the pivotal role of neutrophils and their associated inflammatory responses during AKI-ALI. In vitro, Vanin-1 stimulation enhanced neutrophil activation and NETs formation. Pharmacological inhibition of Vanin-1 with RR6 significantly improved oxygenation, reduced lung injury, and attenuated oxidative stress and inflammation in AKI-ALI mice. Vanin-1 contributes to AKI-ALI progression by promoting NETs formation, oxidative stress, and inflammation. Both genetic deletion and pharmacological inhibition of Vanin-1 effectively alleviated lung injury, highlighting Vanin-1 as a promising therapeutic target for AKI-ALI.
Liu et al. (Fri,) studied this question.