Selective blockade of lysophosphatidic acid LPA 3 receptors reduces murine renal ischemia-reperfusion injury
2003; American Physical Society; Volume: 285; Issue: 3 Linguagem: Inglês
10.1152/ajprenal.00023.2003
ISSN1931-857X
AutoresMark D. Okusa, Hong Ye, Liping Huang, Laura Sigismund, Timothy L. Macdonald, Kevin R. Lynch,
Tópico(s)Peroxisome Proliferator-Activated Receptors
ResumoLysophosphatidic 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.
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