Proximal tubule sphingosine kinase-1 has a critical role in A 1 adenosine receptor-mediated renal protection from ischemia

Abstract

Renal ischemiareperfusion 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 ischemiareperfusion 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 (S1P1 Rf/f PEPCK Cre/) were not protected against renal ischemiareperfusion 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 ischemiareperfusion injury. © 2012 International Society of Nephrology.