Sphingosine-1-Phosphate Evokes Unique Segment-Specific Vasoconstriction of the Renal Microvasculature

Abstract

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, has been implicated in regulating vascular tone and participating in chronic and acute kidney injury. However, little is known about the role of S1P in the renal microcirculation. Here, we directly assessed the vasoresponsiveness of preglomerular and postglomerular microvascular segments to exogenous S1P using the in vitro blood-perfused juxtamedullary nephron preparation. Superfusion of S1P (0.001-10 mM) evoked concentration-dependent vasoconstriction in preglomerular microvessels, predominantly afferent arterioles. After administration of 10 mM S1P, the diameter of afferent arterioles decreased to 35%65% of the control diameter, whereas the diameters of interlobular and arcuate arteries declined to 50%612% and 68%66% of the control diameter, respectively. Notably, efferent arterioles did not respond to S1P. The S1P receptor agonists FTY720 and FTY720-phosphate and the specific S1P1 receptor agonist SEW2871 each evoked modest afferent arteriolar vasoconstriction. Conversely, S1P2 receptor inhibition with JTE-013 significantly attenuated S1P-mediated afferent arteriolar vasoconstriction. Moreover, blockade of L-type voltage-dependent calcium channels with diltiazem or nifedipine attenuated S1P-mediated vasoconstriction. Intravenous injection of S1P in anesthetized rats reduced renal blood flow dose dependently. Western blotting and immunofluorescence revealed S1P1 and S1P2 receptor expression in isolated preglomerular microvessels and microvascular smooth muscle cells. These data demonstrate that S1P evokes segmentally distinct preglomerular vasoconstriction via activation of S1P1 and/or S1P2 receptors, partially via L-type voltagedependent calcium channels. Accordingly, S1P may have a novel function in regulating afferent arteriolar resistance under physiologic conditions. 25: 177425: -178525: , 201425: . doi: 10.1681 Sphingosine 1-phosphate (S1P) is recognized as an important signaling molecule in diverse biologic processes. 1,2 Growing evidence indicates that S1P plays an important role in regulating vascular reactivity. 3-5 S1P is a bioactive sphingolipid metabolite and is released from erythrocytes, platelets, and endothelial cells. 6,7 The majority of S1P effects are mediated via five distinct receptors (S1P1-S1P5 receptors), which represent a family of small G proteincoupled receptors (GPCRs) 5 ; however, S1P can also exist in the cytoplasm as a second messenger involved in Ca 2+ mobilization or cell survival and proliferation. 8,9 S1P1-S1P3 receptors are expressed by a wide variety of tissues, whereas S1P4 and S1P5 receptors are mainly expressed in cells of the immune and nervous systems. 4,10 In the vasculature, endothelial cells mainly express S1P1 and S1P3 with variable expression of S1P2, whereas vascular smooth muscle cells express S1P2 and S1P3 with variable expression of S1P1. [3][4][5] Studies in animals show that application of exogenous S1P J Am Soc Nephrol

Sphingosine‐1‐phosphate and renal vasoconstriction

“…In a previous study, authors demonstrated that the renal vascular bed was endowed with functional S1P 1-2 receptors 2 that mediated vasoconstriction which was attenuated by L-type calcium channel blockers. 2 Thus, the present contribution provides a confirmation of the role for voltage-gated calcium influx and further extends observations to show that intracellular calcium stores are less important for the response, that Rho-kinase is involved in signal transmission as in retinal arterioles 4 and that blockers of reactive oxygen species attenuated S1P responsiveness. Other studies suggest that this pathway may contribute to resting renal vascular tone as renal blood flow was increased in S1P 2 receptor knockouts and addition of S1P 2 receptor antagonists increased afferent arteriolar diameter at baseline conditions.…”

“…1 New information on S1P signalling of potential therapeutic relevance is obtained, and the general concept is confirmed that renal pre-glomerular vascular reactivity relies significantly on calcium influx through voltage-gated calcium channels. The authors showed previously that S1P caused selective renal afferent but not efferent vasoconstriction, 2 and in conjunction with increased S1P release in pathophysiological situations like sepsis and ischaemia-reperfusion incidents, this effect could be relevant in acute kidney injury with parallel decreases in renal blood flow and GFR. Control of renal vascular resistance is physiologically important for the maintenance of stable renal blood flow and glomerular filtration rate.…”

“…Other studies suggest that this pathway may contribute to resting renal vascular tone as renal blood flow was increased in S1P 2 receptor knockouts and addition of S1P 2 receptor antagonists increased afferent arteriolar diameter at baseline conditions. 2,8 Are the present observations representative for the whole population of nephrons as the observations are based on the 5%-10% juxtamedullary nephrons that supply the medulla with blood and have long muscular efferent arterioles and long loops of Henle? Based on the observation that total renal blood flow was lowered by S1P infusion, other vascular units are likely to contribute.…”

“…S1P circulates in plasma in high nanomolar/micromolar concentration range, likely derived from red blood cells and platelets, and displays a high protein binding and is also contained in high-density lipoprotein, HDL, particles. Once released to the extracellular fluid, S1P can interact with specific G protein-coupled receptors with five known members (S1P [1][2][3][4][5] ) that transduce signals via G i , G q and G 12 . S1P receptors 1-3 are present in vascular tissue.…”

Pharmacologic Targeting of Sphingosine-1-Phosphate Receptor 1 Improves the Renal Microcirculation during Sepsis in the Mouse

“…Interestingly, selective deletion of endothelial S1P1 (Ham et al, 2014) or proximal tubule S1P1 (Bajwa et al, 2010) exacerbates renal ischemia/reperfusion injury, suggesting a cross-talk between the renal microvasculature and tubular epithelium during renal ischemia, which has also been suggested to occur during sepsis (Mayeux and Macmillan-Crow, 2012). Recent studies in the kidney also suggest that S1P could be a physiologic regulator of preglomerular vascular tone (Guan et al, 2014).…”