Abstract
Agonists of the sphingosine-1-phosphate receptor (S1PR) attenuate kidney ischemia-reperfusion injury (IRI). Previous studies suggested that S1P 1R-induced lymphopenia mediates this protective effect, but lymphocyte-independent mechanisms could also contribute. Here, we investigated the effects of S1PR agonists on kidney IRI in mice that lack T and B lymphocytes (Rag-1 knockout mice). Administration of the nonselective S1PR agonist FTY720 or the selective S1P1R agonist SEW2871 reduced injury in both Rag-1 knockout and wild-type mice. In vitro, SEW2871 significantly attenuated LPS- or hypoxia/reoxygenation-induced apoptosis in cultured mouse proximal tubule epithelial cells, supporting a direct protective effect of S1P1R agonists via mitogen-activated protein kinase and/or Akt pathways. S1P 1Rs in the proximal tubule mediated IRI in vivo as well: Mice deficient in proximal tubule S1P1Rs experienced a greater decline in renal function after IRI than control mice and their kidneys were no longer protected by SEW2871 administration. In summary, S1PRs in the proximal tubule are necessary for stress-induced cell survival, and S1P1R agonists are renoprotective via direct effects on the tubule cells. Selective agonists of S1P1Rs may hold therapeutic potential for the prevention and treatment of acute kidney injury.
| Original language | English |
|---|---|
| Pages (from-to) | 955-965 |
| Number of pages | 11 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 21 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2010 Jun 1 |
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ASJC Scopus subject areas
- Nephrology
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Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury. / Bajwa, Amandeep; Jo, Sang Kyung; Ye, Hong; Huang, Liping; Dondeti, Krishna R.; Rosin, Diane L.; Haase, Volker H.; Macdonald, Timothy L.; Lynch, Kevin R.; Okusa, Mark D.
In: Journal of the American Society of Nephrology, Vol. 21, No. 6, 01.06.2010, p. 955-965.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury
AU - Bajwa, Amandeep
AU - Jo, Sang Kyung
AU - Ye, Hong
AU - Huang, Liping
AU - Dondeti, Krishna R.
AU - Rosin, Diane L.
AU - Haase, Volker H.
AU - Macdonald, Timothy L.
AU - Lynch, Kevin R.
AU - Okusa, Mark D.
PY - 2010/6/1
Y1 - 2010/6/1
N2 - Agonists of the sphingosine-1-phosphate receptor (S1PR) attenuate kidney ischemia-reperfusion injury (IRI). Previous studies suggested that S1P 1R-induced lymphopenia mediates this protective effect, but lymphocyte-independent mechanisms could also contribute. Here, we investigated the effects of S1PR agonists on kidney IRI in mice that lack T and B lymphocytes (Rag-1 knockout mice). Administration of the nonselective S1PR agonist FTY720 or the selective S1P1R agonist SEW2871 reduced injury in both Rag-1 knockout and wild-type mice. In vitro, SEW2871 significantly attenuated LPS- or hypoxia/reoxygenation-induced apoptosis in cultured mouse proximal tubule epithelial cells, supporting a direct protective effect of S1P1R agonists via mitogen-activated protein kinase and/or Akt pathways. S1P 1Rs in the proximal tubule mediated IRI in vivo as well: Mice deficient in proximal tubule S1P1Rs experienced a greater decline in renal function after IRI than control mice and their kidneys were no longer protected by SEW2871 administration. In summary, S1PRs in the proximal tubule are necessary for stress-induced cell survival, and S1P1R agonists are renoprotective via direct effects on the tubule cells. Selective agonists of S1P1Rs may hold therapeutic potential for the prevention and treatment of acute kidney injury.
AB - Agonists of the sphingosine-1-phosphate receptor (S1PR) attenuate kidney ischemia-reperfusion injury (IRI). Previous studies suggested that S1P 1R-induced lymphopenia mediates this protective effect, but lymphocyte-independent mechanisms could also contribute. Here, we investigated the effects of S1PR agonists on kidney IRI in mice that lack T and B lymphocytes (Rag-1 knockout mice). Administration of the nonselective S1PR agonist FTY720 or the selective S1P1R agonist SEW2871 reduced injury in both Rag-1 knockout and wild-type mice. In vitro, SEW2871 significantly attenuated LPS- or hypoxia/reoxygenation-induced apoptosis in cultured mouse proximal tubule epithelial cells, supporting a direct protective effect of S1P1R agonists via mitogen-activated protein kinase and/or Akt pathways. S1P 1Rs in the proximal tubule mediated IRI in vivo as well: Mice deficient in proximal tubule S1P1Rs experienced a greater decline in renal function after IRI than control mice and their kidneys were no longer protected by SEW2871 administration. In summary, S1PRs in the proximal tubule are necessary for stress-induced cell survival, and S1P1R agonists are renoprotective via direct effects on the tubule cells. Selective agonists of S1P1Rs may hold therapeutic potential for the prevention and treatment of acute kidney injury.
UR - http://www.scopus.com/inward/record.url?scp=77952985501&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952985501&partnerID=8YFLogxK
U2 - 10.1681/ASN.2009060662
DO - 10.1681/ASN.2009060662
M3 - Article
C2 - 20338995
AN - SCOPUS:77952985501
VL - 21
SP - 955
EP - 965
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 6
ER -