Vasopressin lowers renal epoxyeicosatrienoic acid levels by activating soluble epoxide hydrolase.
Activation of the thick ascending limb (TAL) Na+-K+-2Cl-cotransporter (NKCC2) by the antidiuretic hormone arginine vasopressin (AVP) is an essential mechanism of renal urine concentration and contributes to extracellular fluid and electrolyte homeostasis. AVP effects in the kidney are modulated by locally and/or by systemically produced epoxyeicosatrienoic acid derivates (EET). The relation between AVP and EET metabolism has not been determined. Here, we show that chronic treatment of AVP-deficient Brattleboro rats with the AVP V2 receptor analog desmopressin (dDAVP; 5 ng/h, 3 days) significantly lowered renal EET levels (-56 ± 3% for 5,6-EET, -50 ± 3.4% for 11,12-EET, and -60 ± 3.7% for 14,15-EET). The abundance of the principal EET-degrading enzyme soluble epoxide hydrolase (sEH) was increased at the mRNA (+160 ± 37%) and protein levels (+120 ± 26%). Immunohistochemistry revealed dDAVP-mediated induction of sEH in connecting tubules and cortical and medullary collecting ducts, suggesting a role of these segments in the regulation of local interstitial EET signals. Incubation of murine kidney cell suspensions with 1 μM 14,15-EET for 30 min reduced phosphorylation of NKCC2 at the AVP-sensitive threonine residues T96 and T101 (-66 ± 5%; P < 0.05), while 14,15-DHET had no effect. Concomitantly, isolated perfused cortical thick ascending limb pretreated with 14,15-EET showed a 30% lower transport current under high and a 70% lower transport current under low symmetric chloride concentrations. In summary, we have shown that activation of AVP signaling stimulates renal sEH biosynthesis and enzyme activity. The resulting reduction of EET tissue levels may be instrumental for increased NKCC2 transport activity during AVP-induced antidiuresis.
Department of Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Christin
C
Boldt
Department of Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Tom
T
Röschel
Department of Physiology, Christian-Albrechts-University, Kiel, Germany.
Nina
N
Himmerkus
Department of Physiology, Christian-Albrechts-University, Kiel, Germany.
Allein
A
Plain
Department of Physiology, Christian-Albrechts-University, Kiel, Germany.
Markus
M
Bleich
Department of Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Robert
R
Labes
Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
Maximilian
M
Blum
Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Hans
H
Krause
Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Ahmed
A
Magheli
Department of Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Torsten
T
Giesecke
Department of Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Kerim
K
Mutig
Lipidomix, Berlin, Germany.
Michael
M
Rothe
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
Steven M
SM
Weldon
Department of Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany; and.|Berlin Institute of Health, Berlin, Germany.
Duska
D
Dragun
Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
Wolf-Hagen
WH
Schunck
Department of Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Sebastian
S
Bachmann
Department of Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany; and alexander.paliege@charite.de.|Berlin Institute of Health, Berlin, Germany.
Alexander
A
Paliege
D000818:Animals; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology*; D015777:Eicosanoids / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011910:Rats, Brattleboro; D064466:Solute Carrier Family 12, Member 1 / Q000378:metabolism*
D015777:Eicosanoids; D064466:Solute Carrier Family 12, Member 1; D004851:Epoxide Hydrolases; D003894:Deamino Arginine Vasopressin
NKCC2; thick ascending limb; urine concentration mechanism