Expression and function of CXCL12/CXCR4 in rat urinary bladder with cyclophosphamide-induced cystitis

Arms, Lauren; Girard, Beatrice M.; Vizzard, Margaret A.

doi:10.1152/ajprenal.00628.2009

Cited by 64 publications

(132 citation statements)

References 79 publications

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“…Bladder function testing using conscious cystometry demonstrated increased voiding frequency following RVS. A disrupted barrier function of the urothelium could underlie increased voiding frequency via activation of the suburothelial nerve plexus (2,5,21). Animal models of cystitis produce dramatic increases in EB levels in the urinary bladder, indicative of a leaky urothelial barrier (35,60).…”

Section: Urothelial Barrier Is Intact After Rvsmentioning

confidence: 99%

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

Merrill

Malley

Vizzard

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Merrill L, Malley S, Vizzard MA. Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression. Am J Physiol Regul Integr Comp Physiol 305: R147-R156, 2013. First published May 8, 2013 doi:10.1152/ajpregu.00089.2013.-Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) in humans, but mechanisms contributing to symptom worsening are unknown. These studies address stress-induced changes in the structure and function of the micturition reflex using an animal model of stress in male rats. Rats were exposed to 7 days of repeated variate stress (RVS). Target organ (urinary bladder, thymus, adrenal gland) tissues were collected and weighed following RVS. Evans blue (EB) concentration and histamine, myeloperoxidase (MPO), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), and CXCL12 protein content (ELISA) were measured in the urinary bladder, and somatic sensitivity of the hindpaw and pelvic regions was determined following RVS. Bladder function was evaluated using continuous, open outlet intravesical infusion of saline in conscious rats. Increases in body weight gain were significantly (P Յ 0.01) attenuated by day 5 of RVS, and adrenal weight was significantly (P Յ 0.05) increased. Histamine, MPO, NGF, and CXCL12 protein expression was significantly (P Յ 0.01) increased in the urinary bladder after RVS. Somatic sensitivity of the hindpaw and pelvic regions was significantly (P Յ 0.01) increased at all monofilament forces tested (0.1-4 g) after RVS. Intercontraction interval, infused volume, and void volume were significantly (P Յ 0.01) decreased after RVS. These studies demonstrate increased voiding frequency, histamine, MPO, NGF, and CXCL12 bladder content and somatic sensitivity after RVS suggesting an inflammatory component to stress-induced changes in bladder function and somatic sensitivity. micturition; stress; nerve growth factor; ELISA; somatic sensitivity STRESS CONTRIBUTES to symptom exacerbation in many disease states, including functional disorders of the urinary bladder such as overactive bladder (OAB) and interstitial cystitis (IC)/ bladder pain syndrome (BPS) (3,38,58,72). Urinary frequency is a common symptom among patients with OAB or IC/BPS, although the end result of frequent voiding may differ [reduce incontinence episodes (OAB) vs. reduce pain with bladder filling (IC/BPS)]. Patients with IC/BPS report symptom worsening during stress, as do patients with other disorders associated with IC/BPS including rheumatoid arthritis, psoriasis, and irritable bowel syndrome (47,72). Symptom worsening during stress may be due, in part, to disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol, through feedback on the HPA axis, normally acts to attenuate inflammation (47); however, abnormalities in the feedback may cause dysregulation of the inflammatory response. Therefore, patients...

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Section: Urothelial Barrier Is Intact After Rvsmentioning

confidence: 99%

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

Merrill

Malley

Vizzard

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…To induce chronic bladder inflammation, CYP was injected (75 mg/kg ip) every third day for 8 days, with euthanasia occurring on the eighth day (3,17,39). To induce acute bladder inflammation, CYP was injected (150 mg/kg ip), with euthanasia occurring 4 or 48 h after injection (3,17,39).…”

Section: Cyp-induced Cystitis In Female Ratsmentioning

confidence: 99%

“…Tissue was frozen in optimal cutting temperature compound, sectioned (20 m) on a freezing cryostat, and mounted directly onto gelled (0.5%) microscope slides (3,14,17). Sections were incubated overnight at room temperature in rabbit anti-pAKT (1:500; D9, Cell Signaling Technology) or rabbit anti-AKT (1:1,000, Cell Signaling Technology) diluted in 1% goat serum and 0.1 M phosphate buffer.…”

Section: Immunohistochemical Localization Of Akt and Pakt In Cryostatmentioning

confidence: 99%

“…The filter was set to an excitation range of 560 -569 nm and an emission range of 610 -655 nm for visualization of Cy3. Images were captured, acquired in tagged image file format, and imported into image-analysis software (Meta Morph, version 4.5r4; University Imaging, Downingtown, PA) (3,14,17). The free-hand drawing tool was used to select the urothelium, and the urothelium was measured in total pixels area (3,14,17).…”

Section: Visualization and Semiquantitative Analyses Of Pakt In Urothmentioning

confidence: 99%

“…Images were captured, acquired in tagged image file format, and imported into image-analysis software (Meta Morph, version 4.5r4; University Imaging, Downingtown, PA) (3,14,17). The free-hand drawing tool was used to select the urothelium, and the urothelium was measured in total pixels area (3,14,17). To evaluate staining in the detrusor smooth muscle, with care taken to avoid nondetrusor structures (e.g., blood vessels, inflammatory cells), a rectangle of fixed dimension (125 ϫ 125 pixels) was placed on the section according to random x and y coordinates.…”

Section: Visualization and Semiquantitative Analyses Of Pakt In Urothmentioning

confidence: 99%

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Role for pAKT in rat urinary bladder with cyclophosphamide (CYP)-induced cystitis

Arms

Vizzard

2011

American Journal of Physiology-Renal Physiology

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-AKT phosphorylation following peripheral nerve injury or inflammation may play a role in somatic pain processes and visceral inflammation. To examine such a role in micturition reflexes with bladder inflammation, we induced bladder inflammation in adult female Wistar rats (200 -300 g) by injecting cyclophosphamide (CYP) intraperitoneally at acute (150 mg/kg; 4 h), intermediate (150 mg/kg; 48 h), and chronic (75 mg/kg; every third day for 10 days) time points. Western blot analyses of whole urinary bladders showed significant increases (P Յ 0.01) in phosphorylated (p) AKT at all time points; however, the magnitude of AKT phosphorylation varied with duration of CYP treatment. Immunohistochemical analyses of pAKT immunoreactivity (pAKT-IR) in cryostat bladder sections demonstrated duration-dependent, significant (P Յ 0.01) increases in pAKT-IR in both the urothelium and detrusor smooth muscle of CYP-inflamed bladders. Additionally, a suburothelial population of pAKT-IR macrophages (CD68-, MAC2-, and F4/ 80-positive) was present in chronic CYP-treated bladders. The functional role of pAKT in micturition was evaluated using open, conscious cystometry with continuous instillation of saline in conjunction with administration of an inhibitor of AKT phosphorylation, deguelin (1.0 g/10 l), or vehicle (1% DMSO in saline) in control (no inflammation) and CYP (48 h)-treated rats. Bladder capacity, void volume, and intercontraction void interval increased significantly (P Յ 0.05) following intravesical instillation of deguelin in CYP (48 h)-treated rats. These results demonstrate increased AKT phosphorylation in the urinary bladder with urinary bladder inflammation and that blockade of AKT phosphorylation in the urothelium improves overall bladder function. urothelium; cystometry; inflammation; deguelin THE SERINE-THREONINE PROTEIN kinase AKT is involved in cellular survival and protection from apoptosis in a number of tissues and organ systems (6,18,25). Recent studies have demonstrated additional roles for activated (phosphorylated; p) AKT in the initiation and maintenance of neuropathic pain and visceral inflammation (53,59,60,71). Immunohistochemical techniques demonstrate AKT activation in pain transducing C-fiber primary afferents and dorsal horn neurons following peripheral neuronal injury or tissue inflammation (26,58,59,60,71). In visceral inflammation, pAKT levels increase in the spinal cord dorsal horn following chemically induced colitis (53). Upstream regulators of pAKT include growth factors such as platelet-derived growth factor, epidermal growth factor, insulin, thrombin, nerve growth factor (NGF), and brainderived neurotrophic factor (BDNF) as well as other physiological stimuli (6,25,68).Diverse growth factors activate AKT (6, 31, 68), and growth factors are increased in the urinary bladder with inflammation (12,47,48,66,70). Specifically, recent studies by Chung et al.(16) demonstrated increases in pAKT levels with cyclophosphamide (CYP)-induced bladder inflammation and determined that inflammation-induced...

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Autonomic dysfunction and plasticity in micturition reflexes in human α‐synuclein mice

Hamill

Tompkins

Girard

et al. 2012

Developmental Neurobiology

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Although often overshadowed by the motor dysfunction associated with Parkinson’s disease (PD), autonomic dysfunction including urinary bladder and bowel dysfunctions are often associated with PD and may precede motoric changes; such autonomic dysfunction may permit early detection and intervention. Lower urinary tract symptoms are common in PD patients and result in significant morbidity. The current studies focus on non-motor symptoms in PD using a transgenic mouse model with overexpression of human α-synuclein, the peptide found in high concentrations in Lewy body neuronal inclusions, the histopathologic hallmark of PD. We examined changes in the physiological, molecular, chemical, and electrical properties of neuronal pathways controlling urinary bladder function in transgenic mice. The results of these studies reveal that autonomic dysfunction (i.e., urinary bladder) can precede motor dysfunction. In addition, mice with human α-synuclein overexpression in relevant neuronal populations is associated with alterations in expression of neurotransmitter/ neuromodulatory molecules (PACAP, VIP, substance P, neuronal NOS) within neuronal pathways regulating bladder function as well as with increased NGF expression in the urinary bladder. Changes in the electrical and synaptic properties of neurons in the major pelvic ganglia that provide postganglionic innervation to urogenital tissues were not changed as determined with intracellular recording. The urinary bladder dysfunction observed in transgenic mice likely reflects changes in peripheral (i.e., afferent) and/or central micturition pathways or changes in the urinary bladder. SYN-OE mice provide an opportunity to examine early events underlying the molecular and cellular plasticity of autonomic nervous system pathways underlying synucleinopathies.

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Expression and function of CXCL12/CXCR4 in rat urinary bladder with cyclophosphamide-induced cystitis

Cited by 64 publications

References 79 publications

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

Role for pAKT in rat urinary bladder with cyclophosphamide (CYP)-induced cystitis

Autonomic dysfunction and plasticity in micturition reflexes in human α‐synuclein mice

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