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Research ArticleDrug Discovery and Translational Medicine

Pharmacologic Targeting of Sphingosine-1-Phosphate Receptor 1 Improves the Renal Microcirculation during Sepsis in the Mouse

Zhen Wang, Clark R. Sims, Naeem K. Patil, Neriman Gokden and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics January 2015, 352 (1) 61-66; DOI: https://doi.org/10.1124/jpet.114.219394
Zhen Wang
Department of Pharmacology and Toxicology (Z.W., C.R.S., N.K.P., P.R.M.) and Department of Pathology (N.G.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Clark R. Sims
Department of Pharmacology and Toxicology (Z.W., C.R.S., N.K.P., P.R.M.) and Department of Pathology (N.G.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Naeem K. Patil
Department of Pharmacology and Toxicology (Z.W., C.R.S., N.K.P., P.R.M.) and Department of Pathology (N.G.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Neriman Gokden
Department of Pharmacology and Toxicology (Z.W., C.R.S., N.K.P., P.R.M.) and Department of Pathology (N.G.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Philip R. Mayeux
Department of Pharmacology and Toxicology (Z.W., C.R.S., N.K.P., P.R.M.) and Department of Pathology (N.G.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Abstract

Microvascular failure is hallmark of sepsis in humans and is recognized as a strong predictor of mortality. In the mouse subjected to cecal ligation and puncture (CLP) to induce a clinically relevant sepsis, renal microvascular permeability increases and peritubular capillary perfusion declines rapidly in the kidney leading to acute kidney injury (AKI). Sphingosine-1-phosphate (S1P) is a key regulator of microvascular endothelial function. To investigate the role of S1P in the development of microvascular permeability and peritubular capillary hypoperfusion in the kidney during CLP-induced AKI, we used a pharmacologic approach and a clinically relevant delayed dosing paradigm. Evans blue dye was used to measure renal microvascular permeability and intravital video microscopy was used to quantitate renal cortical capillary perfusion. The S1P receptor 1 (S1P1) agonist SEW2871 [5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole] and S1P2 antagonist JTE-013 [N-(2,6-dichloro-4-pyridinyl)-2-[1,3-dimethyl-4-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-hydrazinecarboxamide] were administered at the time of CLP and produced a dose-dependent but partial reduction in renal microvascular permeability at 6 hours after CLP. However, neither agent improved capillary perfusion at 6 hours. With delayed administration at 6 hours after CLP, only SEW2871 reversed microvascular permeability when measured at 18 hours. Importantly, SEW2871 also restored capillary perfusion and improved renal function. These data suggest that S1P1 and S1P2 do not regulate the early decline in renal capillary perfusion. However, later in the course of sepsis, pharmacologic stimulation of S1P1, even when delaying therapy until after injury has occurred, improves capillary and renal function, suggesting this approach should be evaluated as an adjunct therapy during sepsis.

Footnotes

    • Received August 14, 2014.
    • Accepted October 28, 2014.
  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK075991]; the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM106419, T32-GM106999]; the National Institutes of Health National Center for Advancing Translational Sciences Clinical and Translational Science Award [Grant UL1-TR000039]; and by the American Heart Association [Grants 10PRE4140065 and 12PRE12040174].

  • dx.doi.org/10.1124/jpet.114.219394.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 352 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 1
1 Jan 2015
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Research ArticleDrug Discovery and Translational Medicine

S1P1 Protects the Renal Microcirculation

Zhen Wang, Clark R. Sims, Naeem K. Patil, Neriman Gokden and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics January 1, 2015, 352 (1) 61-66; DOI: https://doi.org/10.1124/jpet.114.219394

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Research ArticleDrug Discovery and Translational Medicine

S1P1 Protects the Renal Microcirculation

Zhen Wang, Clark R. Sims, Naeem K. Patil, Neriman Gokden and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics January 1, 2015, 352 (1) 61-66; DOI: https://doi.org/10.1124/jpet.114.219394
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