Epoxyeicosatriensäuren sind Ziel der durch das antidiuretische Hormon induzierten Signalgebung im Nierenmark release_bibivpwoonekzl2ot2orzn6otm

Abstract

Maintenance of the osmotic homeostasis by arginin-vasopressin (AVP) mediated antidiuresis requires the coordinated action of renal epithelial and vascular structures. In the thick ascending limb of the loop of Henle, AVP increases the transport activity of the Na+, K+, 2Cl- cotransporter (NKCC2), thereby enabling the generation of the osmotic gradient necessary for urine concentration. AVP also reduces renal medullary blood flow by causing vasoconstriction of glomerular arterioles and descending vasa recta in order to control the gradient. Locally produced epoxyeicosatrienoic acid (EET) regioisomers inhibit TAL transport activity and cause vasodilation of the renal microvasculature to counteract the effects of AVP. We hypothesized that AVP has a regulatory function in determining renal EET levels. To this end we used Brattleboro rats with central diabetes insipidus (DI) due to a hereditary loss-of-function mutation in the AVP-gene. Animals were treated for 3 days with the selective AVP type-2 receptor agonist desmopressin (dDAVP; 5ng/h) to study medullary EET levels by mass spectrometry-based lipidome analysis. Medullary gene expression was analyzed by an Affymetrix mRNA microarray. Treatment of DI rats with dDAVP resulted in the expected drop in urine flow along with increased NKCC2 mRNA (+130 ± 7 %, p<0,05) and protein (+70 ± 5%, p<0,05) levels. Regioisomers of EET were decreased (5,6-EET, -56 ± 3%; 11,12-EET, -50 ± 3,4%; and 14,15-EET, -60 ± 3,7%; p<0,05). Calcium-independent group VIA phospholipase A2 (iPLA2), which reflects EET synthesis, was significantly reduced (mRNA, -30 ± 3; protein, -65 ± 7%; p<0,05), and soluble epoxide hydrolase (sEH), the primary EET-degrading enzyme, was increased (mRNA, +160 ± 37%; protein, +120 ± 26%; p<0,05). The presence of both enzymes in ADH-sensitive nephron segments was confirmed by immunolocalization studies. Functional relevance of 14,15-EET for TAL transport activity was demonstrated in microperfusion studies of isolated murine TAL segments. Administration [...]
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