Altered Caveolar Mediated Purinergic Signaling in Spontaneously Hypertensive Rats with Detrusor Overactivity

Cristofaro, Vivian; Yalla, Subbarao V.; Sullivan, Maryrose P.

doi:10.1016/j.juro.2012.04.100

Cited by 11 publications

(10 citation statements)

References 30 publications

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“…To precisely quantify the co-expression of endothelial and mesenchymal markers, the Duolink In Situ assay (Olink Bioscience, Uppsala, Sweden) was applied [ 17 – 19 ]. The frozen sections were incubated overnight at 4°C with a mixture of primary antibodies, including anti-human CD31 antibody (mouse, 1:20; catalog code: NB600-562) and FSP-1 (rabbit, 1:100; Abcam, Cambridge, UK; catalog code: ab27957), after incubation with blocking buffer solution (Dako, Protein Block Serum-Free).…”

Section: Methodsmentioning

confidence: 99%

Microvascular Injury in Ketamine-Induced Bladder Dysfunction

Lin

Yang

et al. 2016

PLoS ONE

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The pathogenesis of ketamine-induced cystitis (KC) remains unclear. In this study, bladder microvascular injury was investigated as a possible contributing mechanism. A total of 36 KC patients with exposure to ketamine for more than 6 months, and 9 control subjects, were prospectively recruited. All participants completed questionnaires, including the O’Leary–Sant interstitial cystitis symptom index (ICSI) and the interstitial cystitis problem index (ICPI). All KC patients received a urodynamic study and radiological exams. Bladder tissues were obtained from cystoscopic biopsies in the control group and after hydrodistention in the KC group. Double-immunofluorescence staining of N-methyl-d-aspartate receptor subunit 1 (NMDAR1) and the endothelial marker, cluster of differentiation 31 (CD31), was performed to reveal the existence of NMDAR1 on the endothelium. Electron microscopy (EM) was applied to assess the microvascular change in the urinary bladder and to measure the thickening of the basement membrane (BM). A proximity ligation assay (PLA) was used to quantify the co-localization of the endothelial CD31 receptor and the mesenchymal marker [fibroblast-specific protein 1 (FSP-1)]. The Mann–Whitney U test and Spearman’s correlation coefficient were used for statistical analysis. The mean ICSI [14.38 (± 4.16)] and ICPI [12.67 (± 3.54)] scores of the KC group were significantly higher than those (0 and 0, respectively) of the control group (both p < 0.001). The KC patients had decreasing cystometric bladder capacity (CBC) with a mean volume of 65.38 (± 48.67) mL. NMDAR1 was expressed on endothelial cells in both groups under immunofluorescence staining. Moreover, KC patients had significant BM duplication of microvessels in the mucosa of the urinary bladder under EM. The co-expression of the endothelial marker CD31 and mesenchymal marker FSP1 was significantly stained and calculated under PLA. In conclusion, microvascular injury and mesenchymal phenotypic alteration of endothelial cells can potentially contribute to KC-induced bladder dysfunction.

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Section: Methodsmentioning

confidence: 99%

Microvascular Injury in Ketamine-Induced Bladder Dysfunction

Lin

Yang

et al. 2016

PLoS ONE

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“…Research has shown that a large variety of receptors can be expressed in, or translocated to, these structures; thus the caveolae mediated signal transduction may be important for bladder contraction (Li et al, 1995;Lisanti et al, 1994;Shaul & Anderson, 1998). Furthermore, the caveolae have been shown to be involved in urinary bladder disorders such as overactive bladder, bladder hypertrophy and bladder cancer (Cohen et al, 2004;Cristofaro et al, 2012;Fu et al, 2017). A study from 2012 showed a decrease of the caveolae specific protein caveolin-1 in cyclophosphamide-induced (CYP-induced) cystitis (Kim et al, 2012).…”

Section: Caveolaementioning

confidence: 99%

“…Caveolae have also been accredited other functional roles such as endocytosis (Parton & Simons, 2007). During pathological bladder conditions such as detrusor overactivity, the caveolaemediated signalling appears to be altered due to a change in caveolae density (Cristofaro et al, 2012). In this thesis, the plausible involvement of caveolaedependent signalling for the ATP-evoked release of acetylcholine was examined.…”

Section: Functional Roles Of Caveolae In Urinary Bladder Signallingmentioning

confidence: 99%

Effects of caveolae depletion and urothelial denudation on purinergic and cholinergic signaling in healthy and cyclophosphamide-induced cystitis in the rat bladder

Stenqvist

Carlsson

Winder

et al. 2018

Autonomic Neuroscience

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Cholesterol rich membrane invaginations, caveolae, have important roles in various cellular activities, one of them being signal transduction. This signaling pathway seems to be affected during various bladder disorders and the current study aimed to elucidate the plausible involvement of caveolae mediated signal transduction during cyclophosphamide induced cystitis. Furthermore, the urothelial cholinergic part of ATP-evoked contractions and its possible link to caveolae were investigated. Cholinergic, as well as purinergic, contractile responses in rat urinary bladders were examined using a classic organ bath set-up with full-thickness strip preparations or a whole bladder model that enabled luminal administration of substances. Furthermore, sub groups with and without urothelium were examined. The expression of caveolin-1 was also tested using western blot and immunofluorescence. Caveolae cholesterol depletion by methyl-β-cyclodextrin entailed a significant decrease of ATP-evoked bladder contractility. Interestingly, after muscarinic blockade the ATP induced contractions were significantly reduced in the same manner. Furthermore, this atropine-sensitive part of ATP-evoked responses was absent in denuded as well as inflamed bladders. A tendency towards a reduced expression of caveolin-1 was observed in rats with experimental cystitis. The cholinergic part of ATP-induced contractile responses seemed to be affected by urothelium denudation as well as caveolae depletion. Removing one of these structures nullifies the effect of the other, suggesting an important interaction between the urothelium and the caveolar structures. These effects are absent in inflamed animals and might be one pathophysiological aspect behind BPS/IC.

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“…Polyak ’s research has shown that the decreased number of caveolae and caveolin protein expression in hypertrophied bladders may contribute to alterations in signal transduction pathways 29 , whereas Shakirova provided new evidence that rat detrusor hypertrophy due to outflow obstruction led to an increased density of membrane caveolae to promote contraction in response to bradykinin 30 . The decreased caveolae were associated with impaired purinergic signaling in the detrusor 31 . In our transmission electron microscopy experiment, we also found that the density of caveolae and the expression of three structural proteins were down-regulated in the ICCs-DM of diabetic bladders.…”

Section: Discussionmentioning

confidence: 96%

Interaction of Caveolin-3 and HCN is involved in the pathogenesis of diabetic cystopathy

Dong

Song

Zhu

et al. 2016

Sci Rep

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A growing body of research suggests that impaired bladder Cajal-like interstitial cells (ICCs) are a important component in the pathogenesis of diabetes-induced bladder dysfunction, although the molecular mechanisms have not been illustrated completely. The purpose of this study was to examine whether the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in ICCs-DM were responsible for the detrusor weak contractility of Diabetic cystopathy (DCP) and to study the possible mechanism of regulating the expression and function of HCN channels. HCN channels expression were decreased at the mRNA and protein levels. Forskolin (FSK), which can elevate intracellular cAMP levels, increased the density of the hyperpolarization-activated current and intracellular calcium concentration in both normal control (NC) rats and DCP rats, but the sensitivity of FSK on HCN channels was clearly down-regulated in DCP rats. The loss of caveolae and caveolin was in accordance with the decrease in HCN channels. Caveolin-3 co-localizes with and affects the expression and function of HCN. Taken together, these results indicate that the loss of caveolae and HCN channels in ICCs-DM is important in the pathogenesis of DCP. Increasing the number of caveolae to enhance the function of HCN channels may represent a viable target for the pharmacological treatment of DCP.

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Altered Caveolar Mediated Purinergic Signaling in Spontaneously Hypertensive Rats with Detrusor Overactivity

Cited by 11 publications

References 30 publications

Microvascular Injury in Ketamine-Induced Bladder Dysfunction

Microvascular Injury in Ketamine-Induced Bladder Dysfunction

Effects of caveolae depletion and urothelial denudation on purinergic and cholinergic signaling in healthy and cyclophosphamide-induced cystitis in the rat bladder

Interaction of Caveolin-3 and HCN is involved in the pathogenesis of diabetic cystopathy

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