Selective blockade of lysophosphatidic acid LPA3receptors reduces murine renal ischemia-reperfusion injury

Abstract

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, LPA_1-3 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.