Sphingosine-1-Phosphate Receptor 2 Promotes Renal Microvascular Constriction and Kidney Injury Following Renal Ischemia-Reperfusion in Rats

TL;DR

This study shows that S1P receptor 2 contributes to kidney injury after blood flow is restored following a period of reduced blood flow in rats.

Contribution

The study identifies S1PR2 as a key mediator of microvascular dysfunction and kidney injury after ischemia-reperfusion.

Findings

IR increases afferent arteriolar sensitivity to S1P, causing vasoconstriction.

S1PR2 blockade reduces kidney injury and improves vascular tone after IR.

IR upregulates S1PR2 expression and increases S1P content in the kidney.

Abstract

Ischemia-reperfusion (IR) induced acute kidney injury (AKI) features increased renal vascular resistance, which is predominantly regulated by adjustments in afferent arteriolar diameter. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is a potent vasoconstrictor in afferent arterioles. We hypothesized that IR enhanced afferent arteriolar sensitivity to S1P-induced vasoconstriction, thus contributing to renal microvascular dysfunction and kidney injury in AKI. The impact of IR on afferent arteriolar reactivity to S1P was assessed using the in vitro blood-perfused juxtamedullary nephron preparation in male rats subjected to 60 min of bilateral renal arterial ischemia followed by 24 h of reperfusion. Baseline diameter of afferent arterioles declined significantly following IR. S1P evoked concentration-dependent vasoconstriction in both sham and IR rats. However, the S1P concentration-response curve left-shifted after IR and its EC50 reduced by 8-fold (P < 0.05), suggesting enhanced afferent arteriolar reactivity to S1P. S1P receptor 2 (S1PR2) blockade with JTE-013 increased arteriolar diameter by 38 ± 7% following IR contrasted to a 9 ± 3% increase in sham rats (P < 0.05), indicating that endogenous S1P exerts a significant impact on afferent arteriolar tone after IR. Furthermore, IR upregulated mRNA and protein of S1PR2 in isolated preglomerular microvessels and elevated S1P content in kidney homogenates. Conversely, following IR, vasoresponsiveness to S1PR1 agonist, sphingosine, endothelin-1, norepinephrine, and angiotensin II did not differ from sham controls. JTE-013 treatment reduced plasma creatinine, tubular damage, and kidney ROS accumulation in IR rats. These data establish that IR enhances renal microvascular S1P-S1PR2 signaling and promotes kidney sphingolipid metabolites that could negatively affect kidney tissue perfusion, leading to AKI.

Graphical Abstract

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