Stephen A Zderic

The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

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Publications (153)367.37 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Partial bladder outlet obstruction (pBOO)-induced remodeling of bladder detrusor smooth muscle (DSM) is associated with the modulation of cell signals regulating contraction. We analyzed the DSM from obstructed murine urinary bladders for the temporal regulation of RhoA GTPase and Rho-activated kinase (ROCK), which are linked to Ca(2+)-sensitization. In addition, the effects of equibiaxial cell stretch, a condition thought to be associated with pBOO-induced bladder wall smooth muscle hypertrophy and voiding frequency, on the expression of RhoA, ROCK and CPI-17 were investigated. DSM from 1-, 3-, 7-, and 14-day obstructed male mice bladders and benign prostatic hyperplasia (BPH)-induced obstructed human bladders revealed over-expression of RhoA and ROCKβ at the mRNA and protein levels compared to control. Primary human bladder myocytes seeded onto type I collagen-coated elastic silicone membranes were subjected to cyclic equibiaxial stretch, mimicking the cellular mechanical stretch in the bladder in vivo and analyzed for the expression of RhoA, ROCKβ, and CPI-17. Stretch caused a significant increase of RhoA, ROCKβ, and CPI-17 expression. The stretch-induced increase in CPI-17 expression occurs at the transcriptional level and is associated with CPI-17 promoter binding by GATA-6 and NF-κB, the transcription factors responsible for CPI-17 gene transcription. Cell stretch caused by bladder over-distension in pBOO is the likely mechanism for initiating over-expression of the signaling proteins regulating DSM tone.
    American journal of physiology. Cell physiology. 07/2014;
  • Matthew S Christman, Stephen A Zderic, Thomas F Kolon
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    ABSTRACT: We aimed to develop a conversion formula between different calculations for testicular volume asymmetry. Male adolescents with varicoceles who underwent scrotal ultrasound were studied. Two formulas were analyzed: (1) testicular volume differential, TVDiff = (RTV - LTV)/(TTV), and (2) atrophy index, AI = (RTV - LTV)/(RTV). RTV, LTV, and TTV represent the right, left, and total testicular volume. Through transformations and regression a conversion formula between the calculations was derived. Based on 248 ultrasounds, a clear relationship between the two formulas was demonstrated: AI = ln[(1.97 × TVDiff) + 1], (p < 0.0001). Differential testicular volumes can easily be converted from one formula to another with near-perfect accuracy. The formulas are essentially identical and interchangeable.
    Journal of pediatric urology 01/2014; · 1.38 Impact Factor
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    ABSTRACT: Background Clinical epidemiologic studies suggest that once established, voiding dysfunction can become a lifelong condition if not treated correctly early on in life. Biofeedback is one component of a voiding retraining program to help children with voiding dysfunction. Our goal was to compare objective non-invasive urodynamic data obtained during office biofeedback sessions with patient reported voiding symptom scores. Methods Charts of 55 children referred in 2010 for pelvic floor muscle biofeedback therapy for urinary incontinence were retrospectively reviewed. Patients with any anatomic diagnoses were excluded. Forty-seven (86%) females and eight males (14%) with a mean age of 8.2 years made up the cohort. Uroflow curves, voided volumes, and post-void residuals were recorded at each visit and served as objective data. Volumes were normalized as a percentage of expected bladder capacity according to age. The patient reported symptom score and patient reported outcome (improved, no change or worse) served as subjective measures of intervention. Results The primary referral diagnoses were day and night wetting in 37 (67%) and daytime incontinence in 18 (33%) children. A history of urinary tract infection (UTI) was noted in 32 (64%) patients, and 25% were maintained on antibiotic prophylaxis during the study period. Twenty-nine percent were maintained on anticholinergic medication. Patients attended an average of 2.5 biofeedback sessions. Voided volumes and post void residual volumes were unchanged, but 50% of the abnormal uroflow curves normalized over the course of treatment (p < 0.05). However, the patient reported symptom score decreased from 12.8 ± 5.6 to 8.0 ± 6.5 (p < 0.002) over an average follow-up time of 276 days reflecting fewer daytime voiding symptoms. There was no significant change in the patient symptom score component for the night-time wetting. Patient-reported outcomes at the final session of biofeedback were rated an improved in 26 (47%), no change in 15 (27%), worse in three (5%) patients, and not rated in 11 patients (21%). Conclusions Pelvic floor muscle biofeedback is associated with patient-reported improvement in symptoms, reduction in voiding symptom score, and normalization of uroflow curves, but these improvements are not correlated with objective parameters of voided volumes and post-void residual urine obtained during office visits for biofeedback. It is important to identify the most relevant outcome measures for BFB, as insurance coverage for medical interventions that cannot offer outcomes analysis that demonstrates a benefit for the patient will eventually be eliminated.
    Journal of Pediatric Urology. 01/2014;
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    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 one hour, followed by 23 hours 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.
    Journal of Pediatric Urology. 01/2014;
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    ABSTRACT: Approximately 20% of boys with posterior urethral valves develop ESRD; however, few factors associated with the risk of ESRD have been identified. The objective of this study was to determine if renal parenchymal area, defined as the area of the kidney minus the area of the pelvicaliceal system on first postnatal ultrasound, is associated with the risk of ESRD in infants with posterior urethral valves. A retrospective cohort of boys who were diagnosed with posterior urethral valves at less than 6 months of age between 1988 and 2011 and followed for at least 1 year at a free-standing children's hospital was assembled. Cox proportional hazard regression and Kaplan-Meier analysis were used to estimate the association between renal parenchymal area and time to ESRD. Cox models were adjusted for age at presentation, minimum creatinine 1 month after bladder decompression, and vesicoureteral reflux. Sixty patients were followed for 393 person-years. Eight patients developed ESRD. Median renal parenchymal area was 15.9 cm(2) (interquartile range=13.0-21.6 cm(2)). Each 1-cm(2) increase in renal parenchymal area was associated with a lower risk of ESRD (hazard ratio, 0.64; 95% confidence interval, 0.42 to 0.98). The rate of time to ESRD was 10 times higher in boys with renal parenchymal area<12.4 cm(2) than boys with renal parenchymal area≥12.4 cm(2) (P<0.001). Renal parenchymal area could best discriminate children at risk for ESRD when the minimum creatinine in the first 1 month after bladder decompression was between 0.8 and 1.1 mg/dl. In boys with posterior urethral valves presenting during the first 6 months of life, lower renal parenchymal area is associated with an increased risk of ESRD during childhood. The predictive ability of renal parenchymal area, which is available at time of diagnosis, should be validated in a larger, prospectively-enrolled cohort.
    Clinical Journal of the American Society of Nephrology 12/2013; · 5.07 Impact Factor
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    ABSTRACT: We hypothesized that active surveillance of the adolescent varicocele was not associated with a high prevalence of suboptimal semen analysis (SA) and that those with abnormal SA had smaller testicular volumes and larger volume differentials. An IRB-approved retrospective cohort study of adolescents with a clinically detected varicocele was conducted. Patients were initially observed with serial scrotal ultrasounds (ScrUS) evaluating testicular size and differential. SA was routinely collected in Tanner V individuals, around age 18 years. Prevalence of normal SA parameters was calculated and logistic regression was used to model the ability of age at presentation and testicular volume parameters to predict a normal SA. A cohort of 73 patients underwent surveillance with a mean (SD) age at presentation of 15.5 (2.3) years. Median follow-up was 2.7 years during which time subjects received a median of 3 ScrUS. A low total motile count (TMC) was found in 66% (48/73). Neither age at presentation nor testicular volume differential could predict normal semen volume, density, sperm motility, or TMC. Total testicular volume from the final ultrasound predicted TMC (p=0.008), however, the collective observations of volume during the entire period of surveillance could not predict TMC (p=0.847). There is a high prevalence of suboptimal SA in adolescents with a varicocele who are followed with active surveillance. Total testicular volume can predict TMC at the end of adolescence, but not throughout.
    The Journal of urology 11/2013; · 4.02 Impact Factor
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    ABSTRACT: To study the relationship between myosin light chain phosphorylation of the detrusor muscle and spontaneous smooth muscle contractions in a rabbit model of partial outlet obstruction. New Zealand white rabbit urinary bladders were partially obstructed for 2 weeks. Rabbits were euthanized, detrusor muscle strips were hung on a force transducer and spontaneous activity was measured at varying concentrations (0-0.03 μM/L) of the Rho-kinase inhibitors GSK 576371 or 0.01 μM/L Y27632. Basal myosin light chain phosphorylation was measured by 2-D gel electrophoresis in control and GSK 576371-treated strips. Both drugs suppressed the force of spontaneous contractions, whereas GSK 576371 had a more profound effect on the frequency of the contractions. The IC50 values for the inhibition of frequency and force of spontaneous contractions were 0.17 μM/L and 0.023 μM/L for GSK 576371, respectively. The compound significantly decreased the basal myosin light chain phosphorylation from 28.0 ± 3.9% to 13.5 ± 1.9% (P < 0.05). At 0.01 μM/L, GSK 576371 inhibited spontaneous bladder overactivity by 50%, but inhibited carbachol-elicited contractions force by just 25%. These data suggest that Rho-kinase regulation of myosin light chain phosphorylation contributes to the spontaneous detrusor activity induced by obstruction. This finding could have therapeutic implications by providing another therapeutic option for myogenic, overactive bladder.
    International Journal of Urology 08/2013; · 1.73 Impact Factor
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    ABSTRACT: Caldesmon (CaD), a component of smooth muscle thin filaments, binds actin, tropomyosin, calmodulin, and myosin and inhibits actin-activated ATP hydrolysis by smooth muscle myosin. Internal deletions of the chicken CaD functional domain that spans from amino acids (aa) 718 to 731, which corresponds to aa 512-530 including the adjacent aa sequence in mouse CaD, lead to diminished CaD-induced inhibition of actin-activated ATP hydrolysis by myosin. Transgenic mice with mutations of five aa residues (Lys(523) to Gln, Val(524) to Leu, Ser(526) to Thr, Pro(527) to Cys, and Lys(529) to Ser), which encompass the ATPase inhibitory determinants located in exon 12, were generated by homologous recombination. Homozygous (-/-) animals did not develop, but heterozygous (+/-) mice carrying the expected mutations in the CaD ATPase inhibitory domain (CaD mutant) matured and reproduced normally. The peak force produced in response to KCl and electrical field stimulation (EFS) by the detrusor smooth muscle (DSM) from the CaD mutant was high compared to that of the wild type (WT). CaD mutant mice revealed non-voiding contractions during bladder filling on awake cystometry, suggesting that the CaD ATPase inhibitory domain suppresses force generation during the filling phase, and this suppression is partially released by mutations in 50% of CaD in heterozygous. Our data show for the first time a functional phenotype, at the intact smooth muscle tissue and in vivo organ levels, following mutation of a functional domain at the C-terminal region of CaD.
    AJP Renal Physiology 08/2013; · 4.42 Impact Factor
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    ABSTRACT: Barrington's nucleus, in the pons, regulates micturition through spinal projections to preganglionic parasympathetic neurons. The stress neuropeptide, corticotropin-releasing factor (CRF) is prominent in these projections and has an inhibitory influence. Social stress in rats causes urinary retention and abnormal urodynamics resembling those produced by partial bladder outlet obstruction (pBOO) and this is associated with CRF upregulation in Barrington's nucleus. Here we examined the role of CRF in social stress- and pBOO-induced urodynamic dysfunction by assessing the ability of a CRF1 receptor antagonist to alter these effects. Male rats exposed to repeated resident-intruder stress were administered vehicle or a CRF1 antagonist (NBI-30775) daily prior to the stress. Urodynamic function was recorded in the unanesthetized state 72 h after the final stress. NBI-30775 prevented the increased intermicturition interval, micturition volume and bladder capacity produced by social stress, but not the increase in CRF expression in Barrington's nucleus neurons. The urinary dysfunction was also partly prevented by shRNA targeting of CRF in Barrington's nucleus suggesting that stress-induced urinary dysfunction results in part from CRF upregulation in Barrington's nucleus and enhanced postsynaptic effects in the spinal cord. Finally, NBI-30775 improved urodynamic function of rats that had pBOO of 2 week duration when administered daily during the second week, but did not block the increase in CRF expression in Barrington's nucleus neurons. These findings implicate a role for Barrington's nucleus CRF in stress- and pBOO-induced urodynamic changes and suggest that CRF1 antagonists may be useful therapeutic agents for the treatment of urinary dysfunction.
    AJP Regulatory Integrative and Comparative Physiology 04/2013; · 3.28 Impact Factor
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    ABSTRACT: PURPOSE: There is little normative data on semen analyses in youths at risk for, but who do not present with, infertility. Standard practice amongst infertility specialists includes evaluation of two separate semen samples given the degree of within-subject variability. We hypothesize that males transitioning from pediatric to adult care who are at risk for infertility would similarly have this variability. MATERIALS AND METHODS: A retrospective review of patients with a history of cryptorchidism or varicocele who submitted two semen samples for evaluation of fertility potential was conducted. The within-subject coefficient of variation (CV(w)) and intraclass correlation coefficient (ICC) were calculated for each semen parameter to evaluate reproducibility and reliability, respectively. RESULTS: A total of 79 subjects were studied. Mean age ± SD was 18.8 ± 1.2 years (range 17.8 - 24.7). The CV(w) was high for each semen parameter, ranging from 36% for volume and motility to 82% for total motile count (TMC). ICC for a single SA ranged from 0.55 for motility to 0.88 for total count. ICC for TMC was 0.78 [95% CI, 0.67 - 0.85], consistent with substantial reliability. CONCLUSIONS: Although within-patient variability of individual SA parameters was found, overall there was substantial agreement between consecutive semen analyses in this population at risk for infertility -- particularly regarding TMC, which is the most important determinant of fertility from a SA. Therefore, it is possible to appropriately classify some young men based on the result of a single measurement as they transition from pediatric to adult care.
    The Journal of urology 02/2013; · 4.02 Impact Factor
  • Matthew S Christman, Stephen A Zderic, Thomas F Kolon
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    ABSTRACT: PURPOSE: We aimed to determine the relative semen quality of youths with a diagnosis of cryptorchidism (UDT) or varicocele (Vx), as a surrogate for ultimate paternity potential. We hypothesized that youths with a Vx would have a lower risk of subfertility, based on semen analysis (SA), than their counterparts with surgically corrected UDT. MATERIALS AND METHODS: A retrospective review of patients with a history of UDT or Vx was performed. Patients were placed into one of three groups based on their diagnosis: Group1, untreated Vx; Group2, treated bilateral UDT; Group3, treated unilateral UDT. Age and semen parameters (density, volume, count, motility, total motile count (TMC)) were compared for each group. RESULTS: A total of 193 subjects were studied. Median age [IQR] of the group was 18.3 [18.1-19.3], 18.6 [18.3-21.0], 18.5 [18.2-19.6] years, respectively, for Group1 (n=76), Group2 (n=21), and Group3 (n=96). TMC (million sperm) for Group1, Group2, and Group3 was: 14.6 [4.7-29.3], 4.0 [0-38.0], 34.1 [7.6-90.8], respectively. No significant difference existed between the groups for age, volume (p=0.106), or motility (p=0.197). However, density (p=0.0001), count (p=0.0001), and TMC (p=0.0002) all achieved significance; for each of these parameters, a significant difference could be shown between both Group1 vs. Group3 and Group2 vs. Group3, but not between Group1 vs. Group2. CONCLUSIONS: Semen quality of youths with a varicocele more closely resembles that of those with bilateral UDT than those with unilateral UDT. This is very concerning and should challenge current paradigms of management for adolescents with a varicocele.
    The Journal of urology 02/2013; · 4.02 Impact Factor
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    ABSTRACT: Protein kinase C (PKC)-potentiated inhibitory protein of 17 kDa (CPI-17) inhibits myosin light chain phosphatase, altering levels of myosin light chain phosphorylation and Ca(2+)-sensitivity in smooth muscle. In this study we characterized the CPI-17 promoter and identified binding sites for GATA-6 and nuclear factor-kappa B (NF-κB). GATA-6 and NF-κB up-regulated CPI-17 expression in cultured human and mouse bladder smooth muscle (BSM) cells in an additive manner. CPI-17 expression was decreased upon GATA-6 silencing in cultured BSM cells and in BSM from NF-κB knockout (KO) mice. Moreover, force maintenance by BSM strips from KO mice was decreased compared with wild-type. GATA-6 and NF-κB overexpression was associated with CPI-17 overexpression in BSM from men with benign prostatic hyperplasia (BPH)-induced bladder hypertrophy and in a mouse model of bladder outlet obstruction. Thus, aberrant expression of NF-κB and GATA-6 deregulates CPI-17 expression and contractile function of smooth muscle. Our data provide insight into how GATA-6 and NF-κB mediate CPI-17 transcription, PKC-mediated signaling, and BSM remodeling associated with lower urinary tract symptoms in patients with BPH.
    Molecular and cellular biology 12/2012; · 6.06 Impact Factor
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    ABSTRACT: Protein kinase C (PKC) and BK channels are down-regulated in the detrusor smooth muscle (DSM) in partial bladder outlet obstruction (PBOO). DSM from these bladders display increased spontaneous activity. This study examines the involvement of PKC in the regulation of spontaneous and evoked DSM contractions, and whether pharmacologic inhibition of PKC in normal DSM contributes to increased detrusor excitability. Results indicate the PKC inhibitor, bisindolylmaleimide 1 (Bim-1), prevented a decline in the amplitude of spontaneous DSM contractions over time in vitro, and these contractions persist in the presence of tetrodotoxin. Bim-1 also reduced the basal DSM tone, and the ability to maintain force in response to electrical field stimulation (EFS), but did not affect maximum contraction. PKC activator, Phorbol 12, 13-dibutyrate (PDBu), significantly reduced the amplitude, and increased the frequency of spontaneous contractions at low concentrations (10nM), while causing an increase in force at higher concentrations (1µM). Pre-incubation of DSM strips with iberiotoxin (IBTX) prevented the inhibition of spontaneous contractions by PDBu. BK channel openers, isopimaric acid (ISPA), and NS1619 reduced the Bim-1-induced enhancement of spontaneous contractions in DSM strips. Our data suggest that PKC has a biphasic activation profile in the DSM, and that it may play an important role in maintaining the quiescent state of the normal bladder during storage through the effects on BK channel, while helping to maintain force required for bladder emptying. The data also suggests that PKC dysfunction, as seen in PBOO, contributes to detrusor over activity.
    AJP Renal Physiology 12/2012; · 4.42 Impact Factor
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    ABSTRACT: We set out to characterize the voiding phenotypes of male mice to a water avoidance stress (WAS) protocol and compare the molecular changes with those induced by surgically induced partial bladder outlet obstruction (pBOO). Six-week-old male Swiss Webster mice housed with sibling littermates were individually placed on a platform centered in the middle of a water filled basin for 1 hr daily for 4 weeks. A non stressed cohort of sibling littermates served as controls. Measured end points included voiding frequency, voided volume, bladder mass, and in vivo cystometry. Molecular end points included myosin heavy chain (MHC) isoform distribution by PCR, and nuclear translocation of hypoxia inducible factor (HIF1α) and the nuclear factor of activated T-cells (NFAT) by gel shift assay. These molecular endpoints were compared with samples from male mice undergoing anatomic pBOO. WAS resulted in increased average voided volumes and bladder mass, and a decrease in voiding frequency (P < 0.05). The slower MHC A isoform was only expressed in the pBOO group that developed severe hypertrophy. Gel shift assays revealed substantial increases in HIF1-α nuclear translocation in the group subjected to pBOO that developed severe hypertrophy but minimal changes in the pBOO group that developed minimal hypertrophy and the swim stress groups. The WAS model induces moderate bladder wall hypertrophy in the absence of any surgical manipulation.
    Neurourology and Urodynamics 03/2012; 31(7):1185-9. · 2.67 Impact Factor
  • Matthew S Christman, Stephen A Zderic, Thomas F Kolon
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    ABSTRACT: Concordant and discordant presentations of posterior urethral valves (PUV) in twins have been described. Twin gestation may complicate the diagnosis of PUV based on prenatal evaluation. A case series of 2 sets of twin births is presented, each of which was discordant for the diagnosis of PUV. A delay in diagnosis occurred in both cases, despite prenatal ultrasound abnormalities. This delay could result from failed sensitivity of prenatal ultrasound or from postnatal evaluation of the incorrect twin. Caution must be exercised during follow-up of abnormalities identified on prenatal ultrasound in diseases in which there are no external distinguishing characteristics.
    Urology 02/2012; 79(6):1365-7. · 2.42 Impact Factor
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    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.
    AJP Renal Physiology 07/2011; 301(4):F813-22. · 4.42 Impact Factor
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    Stephen A Zderic, Samuel Chacko
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    ABSTRACT: The contractile properties of the urinary bladder are changed by the conditions of normal development and partial bladder outlet obstruction. This change in the contractile phenotype is accompanied by changes in the regulatory cascades and filaments that regulate contractility. This review focuses on such changes during the course of normal development and in response to obstruction. Our goal is to discuss the experimental evidence that has accumulated from work in animal models and correlate these findings with the human voiding phenotype.
    Journal of Cellular and Molecular Medicine 06/2011; 16(2):203-17. · 4.75 Impact Factor
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    ABSTRACT: Hypertrophy occurs in urinary bladder wall smooth muscle (BSM) in men with partial bladder outlet obstruction (PBOO) caused by benign prostatic hyperplasia (BPH) and in animal models of PBOO. Hypertrophied BSM from the rabbit model exhibits down-regulation of caveolin-1, a structural and functional protein of caveolae that function as signaling platforms to mediate interaction between receptor proteins and adaptor and effector molecules to regulate signal generation, amplification, and diversification. Caveolin-1 expression is diminished in PBOO-induced BSM hypertrophy in mice and in men with BPH. The proximal promoter of the human and mouse caveolin-1 (CAV1) gene was characterized, and it was observed that the transcription factor GATA-6 binds this promoter, causing reduced expression of caveolin-1. Furthermore, caveolin-1 expression levels inversely correlate with the abundance of GATA-6 in BSM hypertrophy in mice and human beings. Silencing of GATA6 gene expression up-regulates caveolin-1 expression, whereas overexpression of GATA-6 protein sustains the transcriptional repression of caveolin-1 in bladder smooth muscle cells. Together, these data suggest that GATA-6 acts as a transcriptional repressor of CAV1 gene expression in PBOO-induced BSM hypertrophy in men and mice. GATA-6-induced transcriptional repression represents a new regulatory mechanism of CAV1 gene expression in pathologic BSM, and may serve as a target for new therapy for BPH-induced bladder dysfunction in aging men.
    American Journal Of Pathology 05/2011; 178(5):2236-51. · 4.60 Impact Factor
  • Journal of Urology - J UROL. 01/2011; 185(4).
  • Journal of Urology - J UROL. 01/2011; 185(4).

Publication Stats

2k Citations
367.37 Total Impact Points

Institutions

  • 1990–2014
    • The Children's Hospital of Philadelphia
      • • Department of Urology
      • • Department of Anesthesia and Critical Care Medicine
      Philadelphia, Pennsylvania, United States
  • 2013
    • Naval Medical Center San Diego
      San Diego, California, United States
  • 1997–2011
    • University of Pennsylvania
      • • Division of Urology
      • • Department of Pathobiology
      Philadelphia, PA, United States
  • 2003–2007
    • Drexel University College of Medicine
      • Department of Pharmacology & Physiology
      Philadelphia, PA, United States
  • 1991–2005
    • Hospital of the University of Pennsylvania
      • • Division of Urology
      • • Department of Radiation Oncology
      • • Department of Surgery
      Philadelphia, Pennsylvania, United States
  • 2001
    • Emory University
      Atlanta, Georgia, United States
  • 1996
    • RWTH Aachen University
      • Klinik für Urologie
      Aachen, North Rhine-Westphalia, Germany
  • 1995
    • Catholic University of Korea
      • Department of Urology
      Sŏul, Seoul, South Korea