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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/F1131    most recent 00212.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Wang, W. Articles by Schrier, R. Search for Related Content PubMed PubMed Citation Articles by Wang, W. Articles by Schrier, R.

Prostacyclin in endotoxemia-induced acute kidney injury: cyclooxygenase inhibition and renal prostacyclin synthase transgenic mice

Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Submitted 8 May 2007 ; accepted in final form 16 July 2007

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-PGF₁, the major metabolite of PGI₂, increased. When cyclooxygenase inhibition with indomethacin abolished this rise in 6-keto-PGF₁, 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-PGF₁. 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.

endotoxemia

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