Molecular Response of the Bladder to Obstruction

Kirsch, Andrew J.; Macarak, Edward J.; Chaqour, Brahim; Quinn, Theresa; Zderic, Stephen A.; Flake, Alan W.; Crombleholme, Timothy M.; Adzick, N. Scott; Canning, Douglas A.; Hubbard, Anne M.; Rosenbloom, Joel; Snyder, Howard M.; Howard, Pamela S.

doi:10.1007/978-1-4419-8889-8_15

Cited by 5 publications

(3 citation statements)

References 30 publications

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“…As seen with other experimental models, pBOO resulted in varying degrees of bladder wall hypertrophy, which is reflected in the standard errors we recorded (16,23). These large standard errors lead to a higher number of mice being needed to show significance in a drug trial such as the one we conducted.…”

Section: Discussionmentioning

confidence: 65%

Calcineurin mediates bladder wall remodeling secondary to partial outlet obstruction

Chang

Sliwoski

Butler

et al. 2011

American Journal of Physiology-Renal Physiology

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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.

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Section: Discussionmentioning

confidence: 65%

Calcineurin mediates bladder wall remodeling secondary to partial outlet obstruction

Chang

Sliwoski

Butler

et al. 2011

American Journal of Physiology-Renal Physiology

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“…Mechanistically, the transfer of excessive strain results in the activation of multiple signaling cascades culminating into reprogramming of gene expression and the production of various prohypertrophic and fibrotic growth factors, such as CCN2. The CCN2 is likely to induce ECM protein accumulation, which perturbs the structural relationship between and among smooth muscle fibers and alters their contractility (20). However, the molecular mechanisms whereby mechanical forces regulate the expression of this profibrotic factor are, as yet, unresolved.…”

mentioning

confidence: 99%

“…spina bifida, benign prostatic hyperplasia, etc.) (20). Therefore, this system appears well suited to examine the mechanical regulation of the CCN2 gene in vivo.…”

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confidence: 99%

Mechanical Stretch Modulates the Promoter Activity of the Profibrotic Factor CCN2 through Increased Actin Polymerization and NF-κB Activation

Chaqour

Yang

Sha

2006

Journal of Biological Chemistry

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The connective tissue growth factor known as CCN2 is an inducible, profibrotic molecule that becomes aberrantly expressed in mechanical overload-bearing tissues. In this study, we found that CCN2 gene expression is rapidly induced in cyclically stretched bladder smooth muscle cells (SMCs) in vitro and in the detrusor muscle of a mechanically overloaded bladder in a rat model of experimental urethral obstruction. The activity of CCN2 promoter constructs, transiently transfected into cultured SMCs, was increased (up to 6-fold) by continuous cyclic stretching. Molecular analyses of the CCN2 promoter by serial construct deletions, cis-element mutagenesis, and electrophoretic mobility shift assays revealed that a highly conserved NF-B binding site located within the CCN2 proximal promoter region is responsible for the activation of the promoter by stretch. Chromatin immunoprecipitation assays showed that NF-B binds to the endogenous CCN2 promoter in both stretched cells and mechanically overloaded bladder tissues. Furthermore, stretch-dependent CCN2 promoter activity was significantly reduced upon inhibition of either phosphatidylinositol 3-kinase, p38 stress-activated kinase, or RhoA GTPase and was completely abolished upon inhibition of actin polymerization. Concordantly, actin polymerization was increased in either mechanically stretched cells or overloaded bladder tissues. Incubation of cultured SMCs with a cell-penetrating peptide containing the N-terminal sequence, Ac-EEED, of smooth muscle ␣-actin, altered both actin cytoskeleton organization and stretch-mediated nuclear relocation of NF-B, and subsequently, it reduced CCN2 promoter activity. Thus, mechanical stretch-induced changes in actin dynamics mediate NF-B activation and induce CCN2 gene expression, which probably initiates the fibrotic reactions observed in mechanical overloadassociated pathologies.

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The Relationship Between Urodynamic Bladder Compliance and Urinary Fibrosis Markers in Children With Neurogenic Bladder Dysfunction

UĞURLU,

CANMEMİŞ,

İŞMAN

et al. 2024

Journal of Pediatric Urology

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Molecular Response of the Bladder to Obstruction

Cited by 5 publications

References 30 publications

Calcineurin mediates bladder wall remodeling secondary to partial outlet obstruction

Calcineurin mediates bladder wall remodeling secondary to partial outlet obstruction

Mechanical Stretch Modulates the Promoter Activity of the Profibrotic Factor CCN2 through Increased Actin Polymerization and NF-κB Activation

The Relationship Between Urodynamic Bladder Compliance and Urinary Fibrosis Markers in Children With Neurogenic Bladder Dysfunction

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