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Am J Physiol Renal Physiol (May 27, 2003). doi:10.1152/ajprenal.00023.2003
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Submitted on January 17, 2003
Accepted on May 21, 2003

Selective Blockade of Lysophosphatidic Acid LPA3 Receptors Reduces Murine Renal Ischemia-Reperfusion Injury

Mark D. Okusa1*, Hong Ye1, Liping Huang1, Laura Sigismund1, Timothy Macdonald2, and Kevin R. Lynch3

1 Department of Medicine, University of Virginia, Charlottesville, VA, USA
2 Department of Chemistry, University of Virginia, Charlottesville, VA, USA
3 Department of Pharmacology, University of Virginia, Charlottesville, VA, USA

* To whom correspondence should be addressed. E-mail: mdo7y{at}virginia.edu.

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 (IR) injury. By real-time polymerase chain reaction (PCR). LPA1-3 receptor mRNAs were expressed in mouse renal cortex (C), outer medulla (OM) and inner medulla (IM) 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, VPC12249, reduced IR injury but this protective effect was lost when the antagonist was co-administered with OMPT. Interestingly, delaying administration of VPC12249 until 30 min after the start of reperfusion did not alter its efficacy significantly. We conclude that VPC12249 reduces renal IR injury predominantly by LPA3 receptor blockade and could serve as novel compound in the treatment of ischemia acute renal failure.




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