Selective blockade of lysophosphatidic acid LPA3 receptors reduces murine renal ischemia-reperfusion injury.
Lysophosphatidic acid (LPA) released during ischemia has diverse physiological effects via its G protein-coupled receptors, LPA1, LPA2, and LPA3 (formerly Edg-2, -4, and -7). We tested the hypothesis that selective blockade of LPA receptors affords protection from renal ischemia-reperfusion (I/R) injury. By real-time PCR, LPA1-3 receptor mRNAs were expressed in mouse renal cortex, outer medulla, and inner medulla with the following rank order LPA3 = LPA2 > LPA1. In C57BL/6 mice whose kidneys were subjected to ischemia and reperfusion, treatment with a selective LPA3 agonist, oleoyl-methoxy phosphothionate (OMPT), enhanced injury. In contrast, a dual LPA1/LPA3-receptor antagonist, VPC-12249, reduced I/R injury, but this protective effect was lost when the antagonist was coadministered with OMPT. Interestingly, delaying administration of VPC-12249 until 30 min after the start of reperfusion did not alter its efficacy significantly. We conclude that VPC-12249 reduces renal I/R injury predominantly by LPA3 receptor blockade and could serve as a novel compound in the treatment of ischemia acute renal failure.
Okusa
Mark D
MD
Department of Medicine, University of Virginia, Charlottesville 22908, USA. mdo7y@virginia.edu
Ye
Hong
H
Huang
Liping
L
Sigismund
Laura
L
Macdonald
Timothy
T
Lynch
Kevin R
KR
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005786:Gene Expression Regulation; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D063086:Organothiophosphates / Q000494:pharmacology*; D010712:Phosphatidic Acids / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*
C473891:1-oleoyl-2-O-methyl-rac-glycerophosphothionate; D063086:Organothiophosphates; D010712:Phosphatidic Acids; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid