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Endogenous vasopressin and vasopressin receptor 2 in bladder as anti-diuretic / anti-spasmodic targets for the treatment of multifactorial nocturia

Zabbarova, Irina ; Tyagi, Pradeep ; Ikeda, Youko ; Yan, Xiangyu ; Ginjupally, Visishta ; Percy, Sophia ; Wolf-Johnson, Amanda ; Tyagi, Shachi ; Drake, Marcus and Andersson, Karl Erik LU orcid , et al. (2025) In Continence 16.
Abstract

Nocturia, the urge to wake from sleep to void, is targeted sub-optimally by existing drugs that modulate circadian dysregulation of urine production in kidney without alleviating detrusor overactivity, a key aspect in the multifactorial etiology of nocturia. This study reports age-related upregulation of arginine vasopressin (AVP) synthesis in mouse urinary bladder to counter the concurrent decline in the kidneys’ ability to concentrate urine, another prevalent symptom of nocturia. Adult/aged C57Bl/6 mice of both sexes were anesthetized with isoflurane for bladder permeability experiments and used awake for cystometries with saline and soybean oil. Bladder overactivity was induced by chronic acrolein instillation. AVP and VR expression... (More)

Nocturia, the urge to wake from sleep to void, is targeted sub-optimally by existing drugs that modulate circadian dysregulation of urine production in kidney without alleviating detrusor overactivity, a key aspect in the multifactorial etiology of nocturia. This study reports age-related upregulation of arginine vasopressin (AVP) synthesis in mouse urinary bladder to counter the concurrent decline in the kidneys’ ability to concentrate urine, another prevalent symptom of nocturia. Adult/aged C57Bl/6 mice of both sexes were anesthetized with isoflurane for bladder permeability experiments and used awake for cystometries with saline and soybean oil. Bladder overactivity was induced by chronic acrolein instillation. AVP and VR expression was examined by Western blot and immunofluorescence. Aged mice showed lower urine osmolality relative to adults that coincided with upregulation of urothelial pre-pro AVP synthesis and VR2 expression that would complement the endocrine action of AVP in promoting bladder reabsorption of free water from stored urine. This was evident from the amplified systemic uptake of tritiated water following bladder instillation of AVP or vasopressin receptor 2 (VR2) agonist, desmopressin (dAVP). Fedovapagon, a small molecule VR2 agonist, exerted anti-diuretic action in kidney, surpassing the efficacy of AVP or dAVP in free water reabsorption from stored urine in bladder and dampened detrusor overactivity. Fedovapagon, with its anti-diuretic actions on kidney, augments the therapeutic benefit activating VR2 receptors in urothelium to promote water reabsorption and relax the detrusor. Therefore, bladder VR2 activation by fedovapagon exemplifies a mechanistic paradigm for addressing the multifactorial etiology of nocturia.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aging, Arginine vasopressin, Bladder overactivity, Desmopressin, Fedovapagon
in
Continence
volume
16
article number
102292
publisher
Elsevier
external identifiers
  • scopus:105020278802
ISSN
2772-9737
DOI
10.1016/j.cont.2025.102292
language
English
LU publication?
yes
id
42fec98a-1db5-4dd6-8c34-4a44d5c8c9cd
date added to LUP
2025-12-09 15:19:05
date last changed
2025-12-09 15:19:54
@article{42fec98a-1db5-4dd6-8c34-4a44d5c8c9cd,
  abstract     = {{<p>Nocturia, the urge to wake from sleep to void, is targeted sub-optimally by existing drugs that modulate circadian dysregulation of urine production in kidney without alleviating detrusor overactivity, a key aspect in the multifactorial etiology of nocturia. This study reports age-related upregulation of arginine vasopressin (AVP) synthesis in mouse urinary bladder to counter the concurrent decline in the kidneys’ ability to concentrate urine, another prevalent symptom of nocturia. Adult/aged C57Bl/6 mice of both sexes were anesthetized with isoflurane for bladder permeability experiments and used awake for cystometries with saline and soybean oil. Bladder overactivity was induced by chronic acrolein instillation. AVP and VR expression was examined by Western blot and immunofluorescence. Aged mice showed lower urine osmolality relative to adults that coincided with upregulation of urothelial pre-pro AVP synthesis and VR2 expression that would complement the endocrine action of AVP in promoting bladder reabsorption of free water from stored urine. This was evident from the amplified systemic uptake of tritiated water following bladder instillation of AVP or vasopressin receptor 2 (VR2) agonist, desmopressin (dAVP). Fedovapagon, a small molecule VR2 agonist, exerted anti-diuretic action in kidney, surpassing the efficacy of AVP or dAVP in free water reabsorption from stored urine in bladder and dampened detrusor overactivity. Fedovapagon, with its anti-diuretic actions on kidney, augments the therapeutic benefit activating VR2 receptors in urothelium to promote water reabsorption and relax the detrusor. Therefore, bladder VR2 activation by fedovapagon exemplifies a mechanistic paradigm for addressing the multifactorial etiology of nocturia.</p>}},
  author       = {{Zabbarova, Irina and Tyagi, Pradeep and Ikeda, Youko and Yan, Xiangyu and Ginjupally, Visishta and Percy, Sophia and Wolf-Johnson, Amanda and Tyagi, Shachi and Drake, Marcus and Andersson, Karl Erik and Wein, Alan and Fry, Christopher and Kanai, Anthony}},
  issn         = {{2772-9737}},
  keywords     = {{Aging; Arginine vasopressin; Bladder overactivity; Desmopressin; Fedovapagon}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Continence}},
  title        = {{Endogenous vasopressin and vasopressin receptor 2 in bladder as anti-diuretic / anti-spasmodic targets for the treatment of multifactorial nocturia}},
  url          = {{http://dx.doi.org/10.1016/j.cont.2025.102292}},
  doi          = {{10.1016/j.cont.2025.102292}},
  volume       = {{16}},
  year         = {{2025}},
}