Chronic activation of vasopressin V2 receptor signalling lowers renal medullary oxygen levels in rats.
OBJECTIVE
In the present study, we aimed to elucidate the effects of chronic vasopressin administration on renal medullary oxygen levels.


METHODS
Adult Sprague Dawley or vasopressin-deficient Brattleboro rats were treated with the vasopressin V2 receptor agonist, desmopressin (5 ng/h; 3d), or its vehicle via osmotic minipumps. Immunostaining for pimonidazole and the transcription factor HIF-1α (hypoxia-inducible factor-1α) were used to identify hypoxic areas. Activation of HIF-target gene expression following desmopressin treatment was studied by microarray analysis.


RESULTS
Pimonidazole staining was detected in the outer and inner medulla of desmopressin-treated rats, whereas staining in control animals was weak or absent. HIF-1α immunostaining demonstrated nuclear accumulation in the papilla of desmopressin-treated animals, whereas no staining was observed in the controls. Gene expression analysis revealed significant enrichment of HIF-target genes in the group of desmopressin-regulated gene products (P = 2.6*10(-21) ). Regulated products included insulin-like growth factor binding proteins 1 and 3, angiopoietin 2, fibronectin, cathepsin D, hexokinase 2 and cyclooxygenase 2.


CONCLUSIONS
Our results demonstrate that an activation of the renal urine concentrating mechanism by desmopressin causes renal medullary hypoxia and an upregulation of hypoxia-inducible gene expression.
Department of Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
A
A
Dietrich
S
S
Mathia
H
H
Kaminski
K
K
Mutig
C
C
Rosenberger
R
R
Mrowka
S
S
Bachmann
A
A
Paliege
D000818:Animals; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004195:Disease Models, Animal; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism*; D009593:Nitroimidazoles / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D011910:Rats, Brattleboro; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014667:Vasopressins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009593:Nitroimidazoles; D017483:Receptors, Vasopressin; D014667:Vasopressins; C033815:pimonidazole; D003894:Deamino Arginine Vasopressin; D010100:Oxygen