Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

Saban, Marcia R.; Nguyen, Nhung; Hammond, Timothy G.; Saban, Ricardo

doi:10.1016/s0002-9440(10)61159-5

Cited by 99 publications

(125 citation statements)

References 102 publications

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“…CB2 receptors were up-regulated in some patients; however, this difference was not statistically significant. Here we confirm previous murine data 25 in humans, showing that ␤2 adrenergic receptor mRNA was significantly higher in BPS patients than in controls.…”

Section: Discussionsupporting

confidence: 92%

“…20 Such changes are indicative of the pathophysiological processes taking place during the progression of a disease; therefore some of the causative factors of BPS/IC might be elucidated by uncovering a link between the expression of proteins, mediating neurogenic inflammation, bladder contractility and epithelial permeability. Although there are several studies examining gene expression changes during experimentally induced cystitis in animals, [21][22][23][24][25] human data are scarce. In human BPS patients, the molecular markers for bladder permeability and proteoglycan core proteins have been shown to be down-regulated, 26,27 and there was an increased permeability and decreased tight junction formation of bladder epithelial cell monolayers grown from biopsies in patients with BPS/IC, as compared with cells from normal controls.…”

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confidence: 99%

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MicroRNAs May Mediate the Down-Regulation of Neurokinin-1 Receptor in Chronic Bladder Pain Syndrome

Freire

Burkhard

Kessler

et al. 2010

The American Journal of Pathology

101

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Bladder pain syndrome (BPS) is a clinical syndrome of pelvic pain and urinary urgency-frequency in the absence of a specific cause. Investigating the expression levels of genes involved in the regulation of epithelial permeability , bladder contractility , and inflammation , we show that neurokinin (NK)1 and NK2 tachykinin receptors were significantly down-regulated in BPS patients. Tight junction proteins zona occludens-1 , junctional adherins molecule -1 , and occludin were similarly down-regulated , implicating increased urothelial permeability , whereas bradykinin B 1 receptor , cannabinoid receptor CB1 and muscarinic receptors M3-M5 were up-regulated. Using cellbased models , we show that prolonged exposure of NK1R to substance P caused a decrease of NK1R mRNA levels and a concomitant increase of regulatory micro(mi)RNAs miR-449b and miR-500. In the biopsies of BPS patients , the same miRNAs were significantly increased , suggesting that BPS promotes an attenuation of NK1R synthesis via activation of specific miRNAs. We confirm this hypothesis by identifying 31 differentially expressed miRNAs in BPS patients and demonstrate a direct correlation between miR-449b , miR-500 , miR-328 , and miR-320 and a down-regulation of NK1R mRNA and/or protein levels. Our findings further the knowledge of the molecular mechanisms of BPS , and have relevance for other clinical conditions involving the NK1 receptor. (Am J

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

MicroRNAs May Mediate the Down-Regulation of Neurokinin-1 Receptor in Chronic Bladder Pain Syndrome

Freire

Burkhard

Kessler

et al. 2010

The American Journal of Pathology

101

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“…We believe that this study is the first to demonstrate upregulation of CRF in the urinary bladder and specifically in the urothelium and bladder nerve fibers after CYP-induced cystitis. Previous gene profiling studies have demonstrated upregulation of CRF receptor in the urinary bladder in murine models of cystitis (39). We extend these studies by demonstrating upregulation of CRF in both acute and chronic CYPinduced cystitis as well as by demonstration of increased CRF expression in specific urinary bladder tissues (urothelium and nerve fibers).…”

Section: Discussionsupporting

confidence: 64%

“…However, the present studies demonstrate time-and tissue-dependent upregulation of CRF in bladder reflex pathways with CYP-induced cystitis, but whether or not this upregulation has any functional significance remains to be determined. It may be the case that CRF plays different roles in bladder function during development and inflammatory conditions and may be dependent on the presence of mast cells, as previously suggested (39,50). Clearly, additional functional studies are needed to define the role of CRF in normal and inflamed states.…”

Section: Discussionmentioning

confidence: 91%

“…It is not possible with this present study that focuses solely on CRF and CRF receptor distribution, expression, and plasticity with CYP-induced cystitis, without examining the functional contribution of CRF to LUT reflexes, to attribute a definitive role for CRF in the acute or chronic stages of CYP-induced cystitis. Bladder inflammation can have both acute and chronic stages such as observed in IC, and these stages may induce expression of genes and protein that underlie inflammation, edema, tissue degradation, and tissue remodeling, repair, and adaptive strategies (39). Expression of CRF after acute or chronic CYPinduced cystitis in LUT tissues suggests diverse roles for CRF that remain to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

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Expression of corticotropin-releasing factor and CRF receptors in micturition pathways after cyclophosphamide-induced cystitis

LaBerge¹,

Malley²,

Zvarová³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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ticotropin-releasing factor (CRF) is a prominent neuropeptide involved in micturition reflexes, and different roles in these reflexes have been suggested. These studies examined the expression of CRF in the urinary bladder and lumbosacral sacral parasympathetic nucleus (SPN) in response to cyclophosphamide (CYP)-induced cystitis (4 h, 48 h, or chronic) in rats. The expression of CRF receptors, CRF 1 and CRF2, was examined in urinary bladder from control and CYP-treated rats. Urinary bladder and lumbosacral spinal cord were harvested from rats killed by isoflurane (4%) and thoracotomy. CRF protein expression in whole urinary bladders significantly (P Յ 0.01) increased with 48 h or chronic CYP treatment. CRF immunoreactivity (IR) was increased significantly (P Յ 0.01) in the urothelium and SPN after CYP treatment. CRF IR nerve fibers increased in density in the suburothelial plexus and detrusor smooth muscle whole mounts with CYP-induced cystitis. CRF 2 receptor transcript was expressed in the urothelium or detrusor smooth muscle, and CRF2 receptor expression increased in whole bladder with CYP-treatment, whereas no CRF1 receptor transcript was expressed in either urothelium or detrusor. Immunohistochemical studies demonstrated CRF 2 IR in urinary bladder nerve fibers and urothelial cells from control animals, whereas no CRF 1 IR was observed. These studies demonstrated changes in the expression of CRF in urinary bladder and SPN region with CYPinduced cystitis and CRF receptor (CRF 2) expression in nerve fibers and urothelium in control rats. CRF may contribute to urinary bladder overactivity and altered sensory processing with CYP-induced cystitis. inflammation; sacral parasympathetic nucleus; urothelium; enzymelinked immunosorbet assay THE CHEMICALLY (cyclophosphamide, CYP) induced bladder inflammation model is associated with alterations in neurochemical (57, 61), electrophysiological (66), organizational (62), and functional properties (14) of micturition pathways. These changes may be mediated by chemical mediators (e.g., neurotrophins, cytokines, neuropeptides) produced in the bladder, spinal cord, or dorsal root ganglia with cystitis (5, 27, 57, 59, 61).Corticotropin-releasing factor (CRF) is of particular relevance in the rat, since it is present in descending projections from the pontine micturition center or more specifically from Barrington's nucleus to the sacral parasympathetic nucleus (SPN; see Refs. 30,31,49,56). Historically, Barrington's nucleus has been viewed as the supraspinal switching center that regulates storage and elimination of urine (25,33,41). Recent studies have led to the suggestion that Barrington's nucleus may contain neurons that control a broad range of pelvic organ functions (28,29,34,38,55). CRF is prominently expressed in the descending pathway from Barrington's nucleus to the SPN in the lumbosacral spinal cord, and prominent CRF immunoreactivity (IR) is expressed in the SPN of adult rats (37,53,54). Our recent studies have demonstrated an age-dependent upregulation of CRF IR ...

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Up‐regulation of phosphorylated CREB but not c‐Jun in bladder afferent neurons in dorsal root ganglia after cystitis

Qiao

Vizzard

2003

J of Comparative Neurology

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We examined the changes of two transcription factors, CREB and c-Jun, in dorsal root ganglia (DRG) after acute (8 or 48 hours) or chronic (10 days) cyclophosphamide (CYP)-induced cystitis. Results showed an increase in the number of p-CREB-immunoreactive (-IR) cells in the L1 and L2 DRG (5-7-fold; P < or = 0.05) as well as L6 and S1 DRG (2-4-fold; P < or = 0.05) after acute and chronic cystitis. The number of p-CREB-IR cells in the L4-L5 DRG was not altered with cystitis. The number of c-Jun-IR cells increased in the L1-L2 DRG (L1: 10-fold; L2: 8-fold; P < or = 0.05) only with chronic cystitis, although it increased in the L6-S1 DRG with CYP-induced cystitis of acute (2-3-fold; P < or = 0.05) and chronic (6-10-fold; P < or = 0.05) duration. After CYP treatment, the percentage of bladder afferent cells expressing p-CREB immunoreactivity (3-7-fold; P < or = 0.05) increased in L1, L2, L6, and S1 DRG. The increase occurred 8 hours post-CYP injection and was maintained with chronic cystitis. There were few c-Jun-IR cells in the bladder afferent population. These results demonstrate that CYP induces p-CREB and c-Jun expression in DRG in a time-dependent manner. However, c-Jun expression is not associated with bladder afferent neurons. Resiniferatoxin reduced CYP-induced up-regulation of p-CREB in DRG, suggesting that cystitis can reveal an altered CREB phosphorylation that may be mediated by capsaicin-sensitive bladder afferents. Colocalization of p-CREB and Trk receptor(s) showed that a subpopulation of p-CREB-IR cells expressed p-Trk with cystitis. These results suggest that up-regulation of p-CREB may be mediated by a neurotrophin/Trk signaling pathway.

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Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

Cited by 99 publications

References 102 publications

MicroRNAs May Mediate the Down-Regulation of Neurokinin-1 Receptor in Chronic Bladder Pain Syndrome

MicroRNAs May Mediate the Down-Regulation of Neurokinin-1 Receptor in Chronic Bladder Pain Syndrome

Expression of corticotropin-releasing factor and CRF receptors in micturition pathways after cyclophosphamide-induced cystitis

Up‐regulation of phosphorylated CREB but not c‐Jun in bladder afferent neurons in dorsal root ganglia after cystitis

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