title: Pharmacologic targeting of sphingosine-1-phosphate receptor 1 improves the renal microcirculation during sepsis in the mouse.
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.
authors.affiliation: 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.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Clark R
authors.initials: CR
authors.lastname: Sims
authors.affiliation: 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.
authors.forename: Naeem K
authors.initials: NK
authors.lastname: Patil
authors.affiliation: 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.
authors.forename: Neriman
authors.initials: N
authors.lastname: Gokden
authors.affiliation: 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 prmayeux@uams.edu.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Mayeux
mesh_terms: D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008026:Ligation / Q000009:adverse effects; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects*; D058990:Molecular Targeted Therapy / Q000379:methods*; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D010539:Permeability / Q000187:drug effects; D011677:Punctures / Q000009:adverse effects; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
chemical_list: C471998:JTE 013; D010069:Oxadiazoles; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes