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, 1 mg/kg) in wild-type (WT) mice was associated with stable glomerular filtration rate (GFR) (164.0 ± 16.7 vs. 173.3 ± 6.7 μl/min, P = not significant) as urinary excretion of 6-keto-PGF1α, the major metabolite of PGI2, increased. When cyclooxygenase inhibition with indomethacin abolished this rise in 6-keto-PGF1α, the same low dose of LPS significantly decreased GFR (110.7 ± 12.1 vs. 173.3 ± 6.7 μl/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 that had increased PGIs expression only in the kidney and increased urinary 6-keto-PGF1α. These Tg mice, however, demonstrated endotoxemia-related AKI with low-dose LPS (1 mg/kg) (GFR: 12.6 ± 3.9 vs. 196.5 ± 21.0 μl/min P < 0.01), which did not alter GFR in WT mice (164.0 ± 16.7 vs. 173.3 ± 6.7 μl/min, P = not significant). 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.
Inhaled nitric oxide and acute kidney injury: new insights from observational data
