Abstract 064: Role of Sphingosine-1-phosphate 2 Receptor in Renal Microvascular Function of Renal Ischemia-reperfusion Rats

Renal ischemia-reperfusion (IR) induced acute kidney injury (IR-AKI) is accompanied by increased renal vascular resistance and a dramatic decline in glomerular filtration rate. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, plays a critical role in IR-AKI. Our recent studies established that exogenous S1P is a potent vasoconstrictor in rat afferent arterioles. We postulated that renal IR enhanced sensitivity of afferent arterioles to S1P-induced vasoconstriction via S1P2 receptor activation. The afferent arteriole response to S1P was assessed using the in vitro blood-perfused juxtamedullary nephron preparation. IR rats were induced by 60 min bilateral renal artery occlusion followed by 24 hours reperfusion. Baseline arteriolar diameter decreased significantly in IR (11.9±0.7 vs. 14.7±0.5 μm in sham, n=7, P<0.05). Exogenous S1P evoked concentration-dependent vasoconstriction in sham rats. Increasing S1P (10 -10 -10 -5 M) decreased diameter to 99±1, 95±2, 89±2, 80±3, 58±4, and 34±2% of baseline (n=7), respectively. Renal IR shifted the S1P vasoconstrictor profile to the left. Arteriolar diameter declined to 93±1, 87±1, 76±1, 64±5, 46±5 and 35±4% of baseline (n=7, P<0.05 vs sham at 10 -10 -10 -7 M S1P). S1P2 receptor blockade with JTE-013 markedly increased baseline diameter by 51±13% in IR (P<0.05, vs. 11±3% in shams, n=3-4), suggesting that endogenous S1P exerts a greater influence on arteriolar tonic in IR than in sham. JTE-013 also markedly attenuated the enhanced vasoconstriction to S1P in IR rats. Arteriolar diameter averaged 112±2, 110±1, 114±3, 102±6, 81±6 and 61±10% of control in response to increasing S1P (P<0.05 vs. JTE-013 untreated-IR) similar to JTE-013 treated sham. In contrast, arteriolar responses to Ang II, endothelin-1 or the S1P precursor, sphingosine were unaltered in IR rats. S1P content increased from 1.3±0.4 to 1.9±0.4 pmol/mg protein (~45%) in the cortical tissue of IR rats and 2.2±0.4 to 3.4±0.2 pmol/mg protein (~55%) in the medullary tissue but reduced the plasma S1P concentration from 2.5±0.3 to 1.3±0.1 μM (~50%, P<0.05, n=3). These data establish that renal IR increases sphingolipid metabolites in rat kidneys and enhances renal microvascular S1P signaling, probably via S1P2 receptor activation.