Mechanisms of sphingosine-1-phosphate-mediated vasoconstriction of rat afferent arterioles

Acta Physiol (Oxf). 2018 Feb;222(2):10.1111/apha.12913. doi: 10.1111/apha.12913. Epub 2017 Jul 13.

Abstract

Aim: Sphingosine-1-phosphate (S1P) influences resistance vessel function and is implicated in renal pathological processes. Previous studies revealed that S1P evoked potent vasoconstriction of the pre-glomerular microvasculature, but the underlying mechanisms remain incompletely defined. We postulated that S1P-mediated pre-glomerular microvascular vasoconstriction involves activation of voltage-dependent L-type calcium channels (L-VDCC) and the rho/rho kinase pathway.

Methods: Afferent arteriolar reactivity was assessed in vitro using the blood-perfused rat juxtamedullary nephron preparation, and diameter was measured during exposure to physiological and pharmacological agents.

Results: Exogenous S1P (10-9 -10-5 mol L-1 ) evoked concentration-dependent vasoconstriction of afferent arterioles. Superfusion with nifedipine, a L-VDCC blocker, increased arteriolar diameter by 39 ± 18% of baseline and significantly attenuated the S1P-induced vasoconstriction. Superfusion with the rho kinase inhibitor, Y-27632, increased diameter by 60 ± 12% of baseline and also significantly blunted vasoconstriction by S1P. Combined nifedipine and Y-27632 treatment significantly inhibited S1P-induced vasoconstriction over the entire concentration range tested. In contrast, depletion of intracellular Ca2+ stores with the Ca2+ -ATPase inhibitors, thapsigargin or cyclopiazonic acid, did not alter the S1P-mediated vasoconstrictor profile. Scavenging reactive oxygen species (ROS) or inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity significantly attenuated S1P-mediated vasoconstriction.

Conclusion: Exogenous S1P elicits potent vasoconstriction of rat afferent arterioles. These data also demonstrate that S1P-mediated pre-glomerular vasoconstriction involves activation of L-VDCC, the rho/rho kinase pathway and ROS. Mobilization of Ca2+ from intracellular stores is not required for S1P-mediated vasoconstriction. These studies reveal a potential role for S1P in the modulation of renal microvascular tone.

Keywords: Ca2+ signalling; cyclopiazonic acid; reactive oxygen species; renal microvascular reactivity; tempol; thapsigargin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arterioles / drug effects
  • Arterioles / metabolism*
  • Kidney / blood supply*
  • Kidney / metabolism*
  • Lysophospholipids / metabolism*
  • Lysophospholipids / pharmacology
  • Male
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Renal Circulation / drug effects
  • Renal Circulation / physiology
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Sphingosine / pharmacology
  • Vasoconstriction / drug effects
  • Vasoconstriction / physiology*

Substances

  • Lysophospholipids
  • sphingosine 1-phosphate
  • Sphingosine