Genetic or pharmacologic disruption of the calcineurin-nuclear factor of activated T-cells axis prevents social stress-induced voiding dysfunction in a murine model

C J Long; S Butler; J Fesi; C Frank; D A Canning; S A Zderic

doi:10.1016/j.jpurol.2014.04.002

Genetic or pharmacologic disruption of the calcineurin-nuclear factor of activated T-cells axis prevents social stress-induced voiding dysfunction in a murine model

J Pediatr Urol. 2014 Aug;10(4):598-604. doi: 10.1016/j.jpurol.2014.04.002. Epub 2014 Apr 24.

Authors

C J Long¹, S Butler², J Fesi³, C Frank⁴, D A Canning⁵, S A Zderic⁶

Affiliations

¹ John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA; The Perelman School of Medicine at The University of Pennsylvania, USA. Electronic address: loncg3@email.chop.edu.
² John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA; The Perelman School of Medicine at The University of Pennsylvania, USA. Electronic address: butlers@email.chop.edu.
³ John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA; The Perelman School of Medicine at The University of Pennsylvania, USA. Electronic address: sliwoski@email.chop.edu.
⁴ John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA; The Perelman School of Medicine at The University of Pennsylvania, USA. Electronic address: charles.frank@emory.edu.
⁵ John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA; The Perelman School of Medicine at The University of Pennsylvania, USA. Electronic address: canning@email.chop.edu.
⁶ John W. Duckett Center for Pediatric Urology at The Children's Hospital of Philadelphia, USA. Electronic address: zderic@email.chop.edu.

PMID: 24909609
DOI: 10.1016/j.jpurol.2014.04.002

Abstract

Objective: Social stress can suppress the voiding reflex, with resultant diminished voiding frequency and increased volumes. The calcineurin-NFAT (nuclear factor of activated T cells) pathway is important in memory development. It was hypothesized that interruption of the calcineurin-NFAT pathway might prevent social stress-induced voiding dysfunction.

Methods: Mice were subjected to social stress in an established resident-intruder model for 1 h, followed by 23 h of barrier separation. NFATc3, NFATc4 knockout (KO) and wild-type (WT) mice were studied. At two weeks, voiding patterns were collected; this was followed by sacrifice. Corticotropin-releasing factor (CRF) mRNA expression in Barrington's nucleus (BN) was determined by in-situ hybridization.

Results: Social stress decreased voiding frequency and increased voided volumes in WT strains. At baseline, NFATc3 KO mice showed decreased voids and increased volumes, while the NFATc4 KO mice resisted social stress. However, CRF mRNA increased in WT mice following social stress and was increased at baseline in NFATc3 KO mice. It was found that CRF mRNA did not increase following social stress in NFATc4 KO mice. The administration of CsA to WT mice normalized voiding patterns following social stress, albeit with no effect on CRF mRNA in BN.

Conclusion: Disrupting the calcineurin-NFAT axis by either genetic or pharmacologic approaches confers resistance to the development of social stress-induced voiding and dysfunction.

Keywords: Barrington's nucleus; Corticotropin releasing factor; Nuclear factor of activated T-cells; Social stress; Voiding dysfunction.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcineurin Inhibitors / therapeutic use*
Corticotropin-Releasing Hormone / genetics
Corticotropin-Releasing Hormone / metabolism
Cyclosporine / therapeutic use
Disease Models, Animal
Female
Male
Mice
Mice, Knockout
NFATC Transcription Factors / genetics*
RNA, Messenger / metabolism
Stress, Psychological / complications*
Urination Disorders / etiology*
Urination Disorders / prevention & control*

Substances

Calcineurin Inhibitors
NFATC Transcription Factors
Nfatc4 protein, mouse
RNA, Messenger
transcription factor NF-AT c3
Cyclosporine
Corticotropin-Releasing Hormone

Grants and funding

P50 DK52620/DK/NIDDK NIH HHS/United States