Blockade of sphingosine 1-phosphate receptor 2 signaling attenuates streptozotocin-induced apoptosis of pancreatic beta-cells.
Sphingosine 1-phosphate (S1P) is a potent sphingolipid mediator that acts through five cognate G protein-coupled receptors (S1P(1)-S1P(5)) and regulates many critical biological processes. Recent studies indicated that S1P at nanomolar concentrations significantly reduces cytokine-induced apoptosis of pancreatic beta-cells in which genes for S1P(1)-S1P(4) are co-expressed. However, the S1P receptor subtype(s) involved in this effect remains to be clarified. In this study, we investigated the potential role of S1P(2) in streptozotocin (STZ)-induced apoptosis of pancreatic beta-cells and progression of diabetes. S1P(2)-deficient (S1P(2)(-/-)) mice displayed a greater survive ability, lower blood glucose levels, and smaller numbers of TUNEL-positive apoptotic beta-cells to administration of a high dose of STZ than wild-type (WT) mice. S1P(2)(-/-) mice showed higher insulin/glucose ratios (an index of relative insulin deficiency) and larger insulin-positive islet areas to administration of a low dose of STZ than WT mice. Moreover, administration of JTE-013, a S1P(2)-specific antagonist, to WT mice ameliorated STZ-induced blood glucose elevation and reduced the incidence of diabetes. Our findings indicate that blockade of S1P(2) signaling attenuates STZ-induced apoptosis of pancreatic beta-cells and decreases the incidence of diabetes.
Imasawa
Toshiyuki
T
Department of Internal Medicine, Division of Immunopathology, Clinical Research Center, Chiba-East National Hospital, 673 Nitona, Chuoh, Chiba 260-8712, Japan. imasawa@cehpnet.com
Koike
Kentaro
K
Ishii
Isao
I
Chun
Jerold
J
Yatomi
Yutaka
Y
D000818:Animals; D017209:Apoptosis; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000081025:Sphingosine-1-Phosphate Receptors; D013311:Streptozocin / Q000494:pharmacology*
C471998:JTE 013; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; D013311:Streptozocin