This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Several reports implicated the involvement of sphingosine kinase 1 (SK1)/sphingosine 1-phosphate (S1P) in the mobilization of intracellular Ca2+. However, the exact mechanism is poorly understood. Our early observation using FLIPR Tetra"""""""" to measure the intracellular Ca2+ levels in HEK293 cells stably expressing angiotensin II type 1a (AT1a) receptors and primary rat and murine vascular smooth muscle cells (VSMC), indicates a characteristic pattern of AngII induced increase in intracellular Ca2+ level, an immediate peak followed by a sustained Ca2+ elevation through store operated calcium channels (SOC). Additionally, inhibition, downregulation or genetic deletion of SK1 expression attenuated the first phase and abrogated the second phase of Ca2+ elevation. Moreover, perincubation of the afferent arteriole of the isolated rabbit glomeruli with SK1 inhibitor, dimethylsphingosine (DMS) blocked the sustained elevation of intracellular Ca2+ and vasoconstrictive response of Ang II perfusion. In vivo experiments performed on wild type and SK1KO mice revealed that deletion of SK1 reverses the effect of AngII on glomerular filtration rate (GFR). This has led us to hypothesize that SK1 activation plays a key role in the AngII induced intracellular Ca2+ elevation and thereby regulates AngII-mediated vascular tone and renal microvascular hemodynamic.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR017677-10
Application #
8360386
Study Section
Special Emphasis Panel (ZRR1-RI-5 (01))
Project Start
2011-07-01
Project End
2012-07-18
Budget Start
2011-07-01
Budget End
2012-07-18
Support Year
10
Fiscal Year
2011
Total Cost
$130,076
Indirect Cost
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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