Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury.
Sphingosine-1-phosphate (S1P), produced by sphingosine kinase 1 (SphK1) or kinase 2 (SphK2), mediates biological effects through intracellular and/or extracellular mechanisms. Here we determined a role for these kinases in kidney injury of wild-type mice following ischemia-reperfusion. SphK1 but not SphK2 mRNA expression and activity increased in the kidney following injury relative to sham-operated animals. Although SphK1(-/-) mice had no alteration in renal function following injury, mice with a disrupted SphK2 gene (SphK2(tr/tr)) had histological damage and impaired function. The immune-modulating pro-drug, FTY720, an S1P agonist failed to provide protection in SphK2(tr/tr) mice. Injured kidneys of these mice showed increased neutrophil infiltration and neutrophil chemokine expression along with a 3- to 5-fold increase in expression of the G-protein-coupled receptor S1P(3) compared to heterozygous SphK2(+/tr) mice. Kidney function and reduced vascular permeability were preserved in S1P(3)(-/-) compared to S1P(3)(+/-) mice after ischemia-reperfusion injury, suggesting increased S1P(3) mRNA may play a role in the injury of SphK2(tr/tr) mice. Our study suggests that constitutive expression of SphK2 may contribute to reduced ischemia-reperfusion injury of the kidney, and its absence may enhance injury due to increased neutrophil infiltration and S1P(3) activation. We also confirm that SphK2 is necessary to mediate the protective effects of FTY720.
Jo
Sang-Kyung
SK
Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Bajwa
Amandeep
A
Ye
Hong
H
Vergis
Amy L
AL
Awad
Alaa S
AS
Kharel
Yugesh
Y
Lynch
Kevin R
KR
Okusa
Mark D
MD
D000818:Animals; D000068876:Fingolimod Hydrochloride; D015971:Gene Expression Regulation, Enzymologic; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology* / Q000473:pathology; D008246:Lysophospholipids; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D011409:Propylene Glycols / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D015427:Reperfusion Injury / Q000201:enzymology* / Q000276:immunology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000099157:Sphingosine Kinase
D000068876:Fingolimod Hydrochloride; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D012333:RNA, Messenger; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate