Proximal tubule sphingosine kinase-1 has a critical role in A1 adenosine receptor-mediated renal protection from ischemia.
Renal ischemia-reperfusion injury is a major cause of acute kidney injury. We previously found that renal A(1) adenosine receptor (A(1)AR) activation attenuated multiple cell death pathways including necrosis, apoptosis, and inflammation. Here, we tested whether induction of cytoprotective sphingosine kinase (SK)-1 and sphingosine-1-phosphate (S1P) synthesis might be the mechanism of protection. A selective A(1)AR agonist (CCPA) increased the synthesis of S1P and selectively induced SK1 in mouse kidney and HK-2 cells. This agonist failed to protect SK1-knockout but protected SK2-knockout mice against renal ischemia-reperfusion injury indicating a critical role of SK1 in A(1)AR-mediated renal protection. Inhibition of SK prevented A(1)AR-mediated defense against necrosis and apoptosis in HK-2 cells. A selective S1P(1)R antagonist (W146) and global in vivo gene knockdown of S1P(1)Rs with small interfering RNA completely abolished the renal protection provided by CCPA. Mice selectively deficient in renal proximal tubule S1P(1)Rs (S1P(1)R(f)(/)(f) PEPCK(Cre/-)) were not protected against renal ischemia-reperfusion injury by CCPA. Mechanistically, CCPA increased nuclear translocation of hypoxia-inducible factor-1α in HK-2 cells and selective hypoxia-inducible factor-1α inhibition blocked A(1)AR-mediated induction of SK1. Thus, proximal tubule SK1 has a critical role in A(1)AR-mediated protection against renal ischemia-reperfusion injury.
Department of Anesthesiology, Columbia University, New York, New York 10032-3784, USA.
Sang W
SW
Park
Mihwa
M
Kim
Joo Y
JY
Kim
Kevin M
KM
Brown
Volker H
VH
Haase
Vivette D
VD
D'Agati
H Thomas
HT
Lee
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D007668:Kidney / Q000098:blood supply / Q000293:injuries / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015233:Models, Statistical; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000099157:Sphingosine Kinase
D000241:Adenosine; D058907:Adenosine A1 Receptor Agonists; D017853:Phosphotransferases (Alcohol Group Acceptor); D043682:Receptor, Adenosine A1; D049349:Receptors, Lysosphingolipid; D000099157:Sphingosine Kinase; C058394:2-chloro-N(6)cyclopentyladenosine