Mechanical ventilation induces kidney dysfunction via release of injurious extracellular vesicles

Mechanical ventilation is a life-saving treatment for patients with acute respiratory distress syndrome but carries substantial risks and can exacerbate lung injury, contributing to end-organ damage and thus significantly increasing patient mortality. In this scenario, kidneys are particularly vulnerable, as approximately 50% of invasively ventilated patients develop acute kidney injury. However, the exact mechanisms mediating the crosstalk between lung injury and kidney dysfunction remain poorly understood. Here, we propose extracellular vesicles (EVs) as central mediators of this lung-kidney axis. To specifically explore how mechanical forces at the alveolo-capillary barrier regulate this proposed signaling axis, we studied the release, composition, and impact of circulating EVs on kidney function. In mice ventilated with high tidal volume (HVT) (20 ml/kg bw for 2 h), we observed structural and functional hallmarks of acute kidney injury, including increased kidney weight, creatinine levels, glomerular tuft area, and leukocyte counts in the lower urinary tract compared to low tidal volume (LVT; 7 ml/kg bw) ventilation controls. Glomeruli in HVT mice had a significantly lower filtration slit density and a reduction in tubular diameter. In parallel, plasma EV levels were significantly higher in HVT vs. LVT mice. Similarly, in vitro mechanical stretch of lung endothelial cells increased EV release. EVs from stretched, but not static pulmonary endothelial cells disrupted barrier function in renal glomerular endothelial cells in vitro. In plasma samples of HVT mice, we observed an altered sphingolipid rheostat with high levels of long-chain ceramides and low sphingosine-1-phosphate. Together, these findings identify the release of injurious EVs from stretched endothelial cells as novel candidate mechanism for ventilator-induced kidney injury (VIKI). Targeting EV release or EV-related signaling could offer a novel therapeutic strategy to reduce the risk for VIKI. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.