title: Calcineurin mediates bladder wall remodeling secondary to partial outlet obstruction.
abstract: We hypothesized that the calcineurin-nuclear factor of activated T-cells (NFAT) pathway is activated following partial bladder outlet obstruction (pBOO), which would allow for pharmacologic treatment to prevent the ensuing bladder wall hypertrophy. Using a model of pBOO in male mice, we were able to demonstrate increased nuclear importation of the transcription factors NFAT and myocyte enhanching factor 2 both of which are under control of calcineurin in both the whole bladder wall as well as the urothelium. We further confirmed that this pathway was activated using transgenic mice containing an NFAT-luciferase reporter construct. Mice were randomized following pBOO to treatment with or without cyclosporine A (CsA), a known inhibitor of calcineurin. The bladder-to-body mass ratio (mg bladder wt/g body wt) of 0.95 ± 0.03 in shams increased to 3.1 ± 0.35 following pBOO, and it dropped back to 1.7 ± 0.22 in the CsA+ group (P < 0.001). Luciferase values (RLU) of 1,130 ± 133 in shams increased to 2,010 ± 474 following pBOO and were suppressed to 562 ± 177 in the CsA+ group (P < 0.05). The myosin heavy chain mRNA (A/B) isoform ratio of 0.07 ± 0.03 in shams increased to 1.04 ± 0.19 following pBOO but it diminished to 0.24 ± 0.1 in the CsA+ group (P < 0.001). In vitro whole organ physiology studies demonstrated improved responses in those bladders from mice treated with CsA. The mRNAs for all four known calcineurin-responsive NFAT isoforms are expressed in the bladder wall, although NFATc(3) and NFATc(4) predominate. Both NFATc3 and NFATc4 are expressed in urothelial as well as smooth muscle cells. We conclude that pBOO activates the calcineurin-NFAT pathway and that CsA treatment decreased bladder hypertrophy, shifted the pattern of myosin isoform mRNA expression back toward that seen in normal controls, and resulted in improved in vitro whole organ performance.
authors.affiliation: John W. Duckett Jr. Center for Pediatric Urology at The Children's Hospital of Philadelphia 19104, USA.
authors.forename: Andy Y
authors.initials: AY
authors.lastname: Chang
authors.forename: Joanna
authors.initials: J
authors.lastname: Sliwoski
authors.forename: Stephan
authors.initials: S
authors.lastname: Butler
authors.forename: George
authors.initials: G
authors.lastname: Hearn
authors.forename: Jenny
authors.initials: J
authors.lastname: Lassmann
authors.forename: Samuel
authors.initials: S
authors.lastname: Chacko
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Canning
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Zderic
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000494:pharmacology* / Q000627:therapeutic use; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000096:biosynthesis; D009929:Organ Size / Q000187:drug effects; D001743:Urinary Bladder / Q000033:anatomy & histology / Q000187:drug effects*; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy*
chemical_list: D065095:Calcineurin Inhibitors; D050778:NFATC Transcription Factors; D016572:Cyclosporine; D019703:Calcineurin; D018995:Myosin Heavy Chains