Sepsis-related acute kidney injury (AKI) is the leading cause of AKI in intensive care units. Endotoxin is a primary initiator of inflammatory and hemodynamic consequences of sepsis and is associated with experimental AKI. The present study was undertaken to further examine the role of the endothelium, specifically prostacyclin(PGI₂), in the pathogenesis of endotoxemia-related AKI. A low dose of endotoxin (LPS 1mg/kg) in wild type (WT) mice was associated with stable glomerular filtration rate (GFR)(164.0±16.7µl/min vs 173.3±6.7µl/min, p=NS) as urinary excretion of 6-keto-PGF-1, the major metabolite of PGI₂, increased. When cyclooxygenase inhibition with indomethacin abolished this rise in 6-keto-PGF-1, the same low dose of LPS significantly decreased GFR(110.7±12.1µl/min vs 173.3±6.7µl/min, p<0.05). The same dose of indomethacin did not alter GFR in WT mice. To further study the role of PGI₂ in endotoxemia, renal-specific PGI synthase (PGIs) transgenic (Tg) mice were developed which had increased PGIs expression only in the kdiney and increased urinary 6-keto-PGF-1. These Tg mice, however, demonstrated endotoxemia-related AKI with low dose LPS (1mg/kg)(GFR:12.6±3.9µl/min vs 196.5±21.0µl/min p<0.01) which did not alter GFR in WT mice (164.0±16.7µl/min vs 173.3±6.7µl/min, p=NS). An elevation in renal cAMP, however, suggested an activation of the PGI₂-cAMP-renin system in these Tg mice. Moreover, angiotensin converting enzyme inhibition afforded protection against endotoxin-related AKI in these Tg mice. Thus, endothelial PGIs mediated-PGI₂, as previously shown with endothelial nitric oxide synthase-mediated nitric oxide, contributes to renal protection against endotoxemia-related AKI. This effect may be overridden by excessive activation of the renin-angiotensin system in renal specific PGIs Tg mice.