期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 285, 期 3, 页码 F565-F574出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00023.2003
关键词
VPC-12249; oleoyl-methoxy phosphothionate; kidney; acute renal failure
资金
- NCI NIH HHS [R-01-CA-088994] Funding Source: Medline
- NIDDK NIH HHS [R-01-DK-056223] Funding Source: Medline
- NIGMS NIH HHS [R-01-GM-052722] Funding Source: Medline
Lysophosphatidic acid (LPA) released during ischemia has diverse physiological effects via its G protein-coupled receptors, LPA(1), LPA(2), and LPA(3) (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, LPA(1-3) receptor mRNAs were expressed in mouse renal cortex, outer medulla, and inner medulla with the following rank order LPA(3) = LPA(2) > LPA(1). In C57BL/6 mice whose kidneys were subjected to ischemia and reperfusion, treatment with a selective LPA(3) agonist, oleoyl-methoxy phosphothionate (OMPT), enhanced injury. In contrast, a dual LPA(1)/LPA(3)-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 LPA(3) receptor blockade and could serve as a novel compound in the treatment of ischemia acute renal failure.
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