1999 European Regional Conference Proceeding

May 12 - 16, 1999

Conference: 1999 European Regional Conference
Title: Vasopressin-dependent and independent regulation of aquaporin-2 in rats with central diabetes insipidus
Authors: Promeneur, Dominique; Kwon, Tae-Hwan; Christensen, Birgitte Monster; Frokiaer, Jorgen; Knepper, Mark; Nielsen, Soren
Institutions: University of Aarhus, The Water and Salt Research Center, University of Aarhus, National Institutes of Health
Promeneur, Dominique

Aquaporin-2 (AQP2) expression is regulated by vasopressin. However, recent evidences have indicated the presence of vasopressin-independent signal transduction pathways as well, which may be of major physiological and pathophysiological importance. To evaluate the role of vasopressin-independent pathways in regulation of AQP2 expression, vasopressin-deficient Brattleboro (BB) rats were subjected to different protocols.

Protocol 1. Total AQP2 protein levels in untreated BB rats were compared to levels in normaI Wistar rats. In untreated BB rats total AQP2 protein levels were 52 " 8% (n=11) of the levels in normal Wistar rats (100 " 13%, n=12). These high AQP2 protein levels indicate the presence of a major vasopressin-independent regulation.

Protocol 2. Since lithium-treatment is known to affect the adenylyl cyclase activity BB rats were treated with lithium for 1 month. This resulted in a dramatic downregulation of AQP2 protein levels to 15 " 6% (n=5) of levels in control BB rats (100 " 10%, n=6). This extensive downregulation indicates, that the high AQP2 protein levels in untreated BB rats, depend on the signaling cascade involving adenylyl cyclase and hence cAMP.

Protocol 3. BB rats thirsted for 48 hours showed a marked increase in AQP2 protein levels (156 " 22%, n=11) compared to untreated BB rats (100 " 14%, n=12). AQP2 mRNA levels were also increased after 48 hours of thirsting. This demonstrates that thirsting-induced expression is independent of plasma vasopressin, and supports the view that thirsting induces AQP2 expression, at least partly, via vasopressin-independent mechanisms.

Protocol 4. BB rats treated with a vasopressin V2-receptor antagonist (SR 121463A, 0.4 mg/day, s.c. administration) for 48 hours showed reduced AQP2 levels (protein or mRNA) and an increased urine output. This suggests that there is a systemic vasopressin-like activation of V2 receptors (e.g. oxytocin) in BB rats.

Combined, the present data strongly suggests:

  1. that regulation of AQP2 expression via vasopressin-independent
  2. pathways represents a major pathway,
  3. that the vasopressin-independent signaling may activate or inhibit
  4. the V2-signaling pathways, and
  5. that expression and trafficking of AQP2 can be differentially regulated.

Aquaporin-2 (AQP2) is expressed in the principal cells of the kidney collecting duct and is regulated by vasopressin (AVP). Recent studies have indicated that its expression may also be controlled by factors other than AVP. Promeneur, et al, conducted tests with Brattleboro (BB) rats which have an inherited inability to synthesize AVP. The purpose of their study was to evaluate the role of AVP independent pathways in regulation of AQP2.

Their experiments showed that depriving BB rats of water for 48 hours resulted in an increase in AQP2 expression in association with a significant increased urinary concentration. In addition, BB rats treated with lithium or a vasopressin V2-receptor antagonist showed a decrease in AQP2 expression rats and a significant increase in urine output.

Therefore, the researchers have concluded that there is a molecular pathway other than the AVP pathway that can regulate AQP2 expression in BB rats. These molecular mechanisms may involve vasopressin V2-receptors, and cAMP signal transduction pathways.