First Author | Paliege A | Year | 2012 |
Journal | Am J Physiol Renal Physiol | Volume | 302 |
Issue | 7 | Pages | F865-74 |
PubMed ID | 22218592 | Mgi Jnum | J:182432 |
Mgi Id | MGI:5315635 | Doi | 10.1152/ajprenal.00222.2011 |
Citation | Paliege A, et al. (2012) Group VIA phospholipase A2 is a target for vasopressin signaling in the thick ascending limb. Am J Physiol Renal Physiol 302(7):F865-74 |
abstractText | Na(+)-K(+)-2Cl(-) cotransporter (NKCC2)-mediated NaCl reabsorption in the thick ascending limb (TAL) is stimulated by AVP via V2 receptor/PKA/cAMP signaling. This process is antagonized by locally produced eicosanoids such as 20-HETE or prostaglandin E(2), which are synthesized in a phospholipase A(2)-dependent reaction cascade. Using microarray-based gene expression analysis, we found evidence for an AVP-dependent downregulation of the calcium-independent isoform of PLA(2), iPLA(2)beta, in the outer medulla of rats. In the present study, we therefore examined the contribution of iPLA(2)beta to NKCC2 regulation. Immunoreactive iPLA(2)beta protein was detected in cultured mTAL cells as well as in the entire TAL of rodents and humans with the exception of the macula densa. Administration of the V2 receptor-selective agonist desmopressin (5 ng/h; 3 days) to AVP-deficient diabetes insipidus rats increased outer medullary phosphorylated NKCC2 (pNKCC2) levels more than twofold in association with a marked reduction in iPLA(2)beta abundance (-65%; P < 0.05), thus confirming microarray results. Inhibition of iPLA(2)beta in Sprague-Dawley rats with FKGK 11 (0.5 muM) or in mTAL cells with FKGK 11 (10 muM) or (S)-bromoenol lactone (5 muM) for 1 h markedly increased pNKCC2 levels without affecting total NKCC2 expression. Collectively, these data indicate that iPLA(2)beta acts as an inhibitory modulator of NKCC2 activity and suggest that downregulation of iPLA(2)beta may be a relevant step in AVP-mediated urine concentration. |