Renal ischemia‐reperfusion led to enhanced renal microvascular response to sphingosine‐1‐phosphate

Abstract

Sphingosine‐1‐phosphate (S1P) potently vasoconstricts renal microvessels and participates in ischemia‐reperfusion (IR) induced acute kidney injury (AKI). We postulated that IR enhances renal vascular reactivity to S1P and contributes to AKI. Reactivity of juxtamedullary afferent arterioles (AA) to S1P was assessed in vitro in rats receiving 60 min bilateral ischemia followed by 24 hr reperfusion (B60IR) using the blood‐perfused juxtamedullary nephron technique (n=5–7/group). Plasma creatinine increased in B60IR (3.7±0.2 vs. 1.2±0.1 mg/dl in sham, p<0.05). Baseline AA diameter decreased in B60IR (11.8±0.7 vs. 14.6±0.6 μm in shams, p<0.05). S1P evoked concentration‐dependent AA vasoconstriction in both groups, however, the response was markedly enhanced in B60IR. S1P (10−10–10−5 M) reduced AA diameter to 93±1, 88±1, 76±1, 64±5, 46±5 and 35±4% of control in B60IR vs. 100±1, 94±2, 91±2, 81±4, 59±5 and 32±4%, respectively in shams. Conversely, AA responses to norepinephrine (NE) or KCl were unchanged. NE (10−8–10−6 M) reduced AA diameter to 92±2, 81±5 and 42±8% of control in B60IR compared to 92±2, 78±5 and 34±6% in shams. KCl (30, 60 and 90 mM) decreased AA diameter to 89±4, 51±6 and 40±7% in B60IR vs. 80±4, 38±4 and 32±4% in shams (p>;0.05). These data reveal that IR enhances AA reactivity to S1P and may contribute importantly to IR‐AKI.Funding sources: AHA10SDG3770010, DK44628 and HL074167