Adaptation to sustained high plasma vasopressin in water and electrolyte homeostasis in the rat transgenic for the metallothionein-vasopressin fusion gene

Abstract

Prolonged exposure of tissues to a receptor agonist often leads to adaptive changes that limit the subsequent responsiveness of the tissue to the same agonist. Recently, we have generated rats transgenic for the metallothionein I-human arginine vasopressin (AVP) fusion gene (Tg), which produced high plasma AVP with relatively preserved renal water excretion, suggesting that there might be adaptive mechanism(s) for maintaining water and electrolyte homeostasis against chronic AVP oversecretion from the earliest stage of life. In this study, to investigate whether down-regulation of AVP V2 receptor (V2R), which could possibly be caused by long-standing high plasma AVP, participates in this adaptive mechanism(s), non-peptidic V2R antagonist OPC31260 was administered to reverse the down-regulation, and water loading was performed after V2R antagonist treatment had been withdrawn. Additionally, to confirm the down-regulation, Northern blotting analysis for V2R mRNA was carried out. Tg rats showed slightly decreased urine volume and water intake with an equivalent plasma [Na + ] level (Tg 140·4 0·6 mEq/l; control 139·3 0·6 mEq/l) under basal conditions. After water loading using a liquid diet containing zinc, which stimulates the promoter region in the transgene, the urine increase showed only limited suppression with a dramatically increased plasma AVP level and mild hyponatremia (135·8 1·8 mEq/l) in Tg rats. When diet containing OPC31260 had been provided for 4 days until the day before the start of water loading, antidiuresis and hyponatremia (125·4 1·4 mEq/l) were significantly potentiated. V2R mRNA expression in kidney was significantly less in Tg rats than in control rats under basal conditions, and this suppression was restored by OPC31260 treatment to levels comparable with those of control rats. These results suggest that long-standing high plasma AVP causes V2R down-regulation, and it may play an important role in the adaptive mechanism(s) for maintaining water and electrolyte homeostasis in chronically AVP-overexpressing rats.

Overexpression of vasopressin in the rat transgenic for the metallothionein-vasopressin fusion gene

“…Acute induction of AVP secretion combined with water loading therefore appears to cause diluting hyponatremia in Tg rats. This is supported by Yokoi et al (2002), who revealed a decrease in plasma total protein after the zinc liquid diet.…”

“…The escape involves suppression of aquaporin 2 expression in the collecting duct (Ecelbarger et al 1997), associated with a decrease in V2 receptor mRNA (Murase et al 1999) and protein (Tian et al 2000). We have analyzed the precise mechanisms for such 'vasopressin tolerance' status in Tg rats (Yokoi et al 2002).…”

Altered cardiovascular regulation in arginine vasopressin-overexpressing transgenic rat

“…In the previous study, we examined water and electrolyte metabolism in Tg rats, which is regulated by AVP mainly via V2R in kidney, and showed that there was an adaptive mechanism to prevent water retention caused by sustained hypervasopressinemia (25). Another major action of AVP is vasoconstriction, which is mediated by V1aR in vascular smooth muscle cells.…”

“…In our previous study (25), we successfully restored the downregulation of V2 receptors (V2R) by pretreatment with a V2R antagonist. In the present study, we attempted to restore the downregulation of V1aR by pretreatment with the V1aR antagonist OPC-212168.…”

“…Recently, we (15,25) developed rats transgenic for the fusion gene consisting of the heavy metal-inducible promoter region of the mouse metallothionein I gene and human AVP gene (Tg). Interestingly, the change in water and electrolyte balance was relatively mild despite a markedly elevated plasma AVP level, suggesting that there may be adaptive mechanisms for maintaining water and electrolyte homeostasis against chronic AVP oversecretion from the earliest stage of life.…”