Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury

Sang Kyung Jo; Amandeep Bajwa; Hong Ye; Amy L. Vergis; Alaa S. Awad; Yugesh Kharel; Kevin R. Lynch; Mark D. Okusa

doi:10.1038/ki.2008.400

Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury

Sang Kyung Jo, Amandeep Bajwa, Hong Ye, Amy L. Vergis, Alaa S. Awad, Yugesh Kharel, Kevin R. Lynch, Mark D. Okusa

Research output: Contribution to journal › Article › peer-review

69 Citations (Scopus)

Abstract

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 S1P₃ compared to heterozygous SphK2^+/tr mice. Kidney function and reduced vascular permeability were preserved in S1P₃^-/- compared to S1P₃^+/- mice after ischemia-reperfusion injury, suggesting increased S1P₃ 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 S1P₃ activation. We also confirm that SphK2 is necessary to mediate the protective effects of FTY720.

Original language	English
Pages (from-to)	167-175
Number of pages	9
Journal	Kidney International
Volume	75
Issue number	2
DOIs	https://doi.org/10.1038/ki.2008.400
Publication status	Published - 2009 Jan
Externally published	Yes

Bibliographical note

Funding Information:
We gratefully acknowledge Michael Rouse, MS (Dept of Medicine) for expert technical assistance and helpful discussions, Dr Diane Rosin (Dept of Pharmacology) for careful reading of the paper and helpful discussions, Dr Richard Prioa (NIH) for providing the SphK1 −/− and S1P 3 −/− mice, and Dr V. Brinkmann (Novartis) for providing FTY720. This work was supported by grants from the National Institutes of Health PO1 073361, RO1 DK62324, RO1 DK065957, RO1 HL070065, and R01 GM067958.

Keywords

Acute kidney injury
FTY720
S1P
SphK

ASJC Scopus subject areas

Nephrology

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10.1038/ki.2008.400

Cite this

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title = "Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury",

abstract = "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 SphK2tr/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 S1P3 compared to heterozygous SphK2+/tr mice. Kidney function and reduced vascular permeability were preserved in S1P3-/- compared to S1P3+/- mice after ischemia-reperfusion injury, suggesting increased S1P3 mRNA may play a role in the injury of SphK2tr/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 S1P3 activation. We also confirm that SphK2 is necessary to mediate the protective effects of FTY720.",

keywords = "Acute kidney injury, FTY720, S1P, SphK",

author = "Jo, {Sang Kyung} and Amandeep Bajwa and Hong Ye and Vergis, {Amy L.} and Awad, {Alaa S.} and Yugesh Kharel and Lynch, {Kevin R.} and Okusa, {Mark D.}",

note = "Funding Information: We gratefully acknowledge Michael Rouse, MS (Dept of Medicine) for expert technical assistance and helpful discussions, Dr Diane Rosin (Dept of Pharmacology) for careful reading of the paper and helpful discussions, Dr Richard Prioa (NIH) for providing the SphK1 −/− and S1P 3 −/− mice, and Dr V. Brinkmann (Novartis) for providing FTY720. This work was supported by grants from the National Institutes of Health PO1 073361, RO1 DK62324, RO1 DK065957, RO1 HL070065, and R01 GM067958.",

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AU - Kharel, Yugesh

AU - Lynch, Kevin R.

AU - Okusa, Mark D.

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N2 - 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 SphK2tr/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 S1P3 compared to heterozygous SphK2+/tr mice. Kidney function and reduced vascular permeability were preserved in S1P3-/- compared to S1P3+/- mice after ischemia-reperfusion injury, suggesting increased S1P3 mRNA may play a role in the injury of SphK2tr/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 S1P3 activation. We also confirm that SphK2 is necessary to mediate the protective effects of FTY720.

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Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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