title: Prostacyclin in endotoxemia-induced acute kidney injury: cyclooxygenase inhibition and renal prostacyclin synthase transgenic mice.
abstract: 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 (PGI(2)), 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 microl/min, P = not significant) as urinary excretion of 6-keto-PGF(1alpha), the major metabolite of PGI(2), increased. When cyclooxygenase inhibition with indomethacin abolished this rise in 6-keto-PGF(1alpha), the same low dose of LPS significantly decreased GFR (110.7 +/- 12.1 vs. 173.3 +/- 6.7 microl/min, P < 0.05). The same dose of indomethacin did not alter GFR in WT mice. To further study the role of PGI(2) 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-PGF(1alpha). 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 microl/min P < 0.01), which did not alter GFR in WT mice (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant). An elevation in renal cAMP, however, suggested an activation of the PGI(2)-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 PGI(2), 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.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA. robert.schrier@uchsc.edu).
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Einath
authors.initials: E
authors.lastname: Zolty
authors.forename: Sandor
authors.initials: S
authors.lastname: Falk
authors.forename: Sandra
authors.initials: S
authors.lastname: Summer
authors.forename: Robert
authors.initials: R
authors.lastname: Stearman
authors.forename: Mark
authors.initials: M
authors.lastname: Geraci
authors.forename: Robert
authors.initials: R
authors.lastname: Schrier
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D058186:Acute Kidney Injury / Q000378:metabolism* / Q000382:microbiology* / Q000503:physiopathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004656:Enalapril / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism; D019446:Endotoxemia / Q000150:complications*; D004731:Endotoxins / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000150:complications; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; D008070:Lipopolysaccharides; D015121:6-Ketoprostaglandin F1 alpha; D004656:Enalapril; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D007213:Indomethacin