Distant organ effects of acute kidney injury (AKI) are a leading cause of morbidity and mortality. While little is known about the underlying mechanisms, limited data suggests a role for inflammation. Utilizing a lung candidate gene discovery approach in a mouse model of ischemic AKI induced lung dysfunction, we identified prominent lung activation of 66 apoptosis-related genes at 6 and/or 36 hours (h) following ischemia, of which 6 genes represent the tumor necrosis factor receptor (TNFR) superfamily, and another 23 genes associated with the TNFR pathway. Given that pulmonary apoptosis is an important pathogenic mechanism of acute lung injury (ALI), we hypothesized that AKI leads to pulmonary pro-apoptotic pathways that facilitate lung injury and inflammation. Functional correlation with 1) TUNEL and 2) active caspase-3 (aC3) activity, immunoblot, and immunohistochemistry (IHC) identified kidney IRI-induced pulmonary apoptosis at 24 h, and co-localization studies with CD34 identified predominantly endothelial apoptosis. Mice were treated with caspase inhibitor Z-VAD-FMK (0.25 mg i.p.) or vehicle 1 h prior and 8 h following sham or kidney IRI, and bronchoalveolar (BAL) fluid protein was measured at 36 h as a surrogate for lung leak. Caspase inhibition reduced lung microvascular changes after kidney IRI. The pulmonary apoptosis seen in wild type control mice during AKI was absent in TNFR^-/- mice. Using an initial genomic approach to discovery followed by a mechanistic approach to disease targeting, we demonstrate that pulmonary endothelial apoptosis is a direct mediator of the distant organ dysfunction during experimental AKI .