Role of urinary cations in the aetiology of bladder symptoms and interstitial cystitis

Parsons, C. Lowell; Shaw, Timothy I.; Berecz, Zoltan; Su, Yongxuan; Zupkas, Paul; Argade, Sulabha

doi:10.1111/bju.12603

Cited by 29 publications

(22 citation statements)

References 27 publications

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“…In this model, no overt damage is produced with ChABC and only a mild inflammation and edema is induced by dilute PS. Numerous other studies in the past have indicated that treatments such as HCl (8) or PS (20,30) can increase permeability of the bladder, and others have shown that IC patients have more permeable bladders (2,20,22,24). The role of the GAG layer was inferred.…”

Section: Discussionmentioning

confidence: 94%

“…Typically, only a relatively lowgrade inflammation with some mast cells and neutrophils is present (9,17,31) and a mild inflammatory gene expression profile is seen in IC patients (16), although severe inflammation can sometimes be seen in patients with Hunner's lesion (17). Interestingly, there is credible evidence that excess organic polycations such as protamine or smaller molecules in urine (24,28) or the loss of polyanionic glycosylation of Tamm-Horsfal protein (23) (loss of scavenger function) can damage the GAG layer and, if chronic, could lead to a loss of urothelial terminal differentiation and appearance of symptoms due to chronic increased permeability. Thus the models presented here could be representative of a natural disease process if made chronic.…”

Section: Discussionmentioning

confidence: 99%

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In the absence of overt urothelial damage, chondroitinase ABC digestion of the GAG layer increases bladder permeability in ovariectomized female rats

Hurst

Gordon

Tyler

et al. 2016

American Journal of Physiology-Renal Physiology

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In the absence of overt urothelial damage, chondroitinase ABC digestion of the GAG layer increases bladder permeability in ovariectomized female rats. Am J Physiol Renal Physiol 310: F1074 -F1080, 2016. First published February 24, 2016 doi:10.1152/ajprenal.00566.2015.-Loss of integrity of the protective impermeability barrier in the urothelium has been identified as significant in bladder dysfunction. In this study, we tested the theory that the luminal layer of glycosaminoglycans (GAG) serves as an important component of barrier function. The peptide polycation protamine sulfate (PS), 1 mg/ml, was instilled intravesically for 10 min into rat bladders. Chondroitinase ABC (ChABC), 63 IU/ml, was instilled into an additional six rats for 30 min to digest the GAG layer. Unmanipulated controls and sham-injected controls were also performed. After 24 h, the rats were euthanized, the bladders were removed, and permeability was assessed in the Ussing chamber and by diffusion of FITC-labeled dextran (4 kDa) to measure macromolecular permeability. The status of tight junctions was assessed by immunofluorescence and electron microscopy. In control and sham treated rat bladders, the transepithelial electrical resistance were means of 2.5 Ϯ 1.1 vs. 2.6 Ϯ 1.1 vs 1.2 Ϯ 0.5 and 1.01 Ϯ 0.7 k⍀·cm 2 in the PS-treated and ChABC-treated rat bladders (P ϭ 0.0016 and P ϭ 0.0039, respectively). Similar differences were seen in dextran permeability. Histopathology showed a mild inflammation following PS treatment, but the ChABC-treated bladders were indistinguishable from controls. Tight junctions generally remained intact. ChABC digestion alone induced bladder permeability, confirming the importance of the GAG layer to bladder barrier function and supports that loss of the GAG layer seen in bladder biopsies of interstitial cystitis patients could be a significant factor producing symptoms for at least some interstitial cystitis/painful bladder syndrome patients. urinary bladder; administration; intravesical; cystitis; interstitial; permeability; models; animal INTERSTITIAL CYSTITIS (IC) is a disease of the bladder diagnosed by exclusion on the basis of urgency, frequency, and pain (6). Although the etiology of this disease remains unknown, the evidence suggests that there is disruption of the urothelium that could result in enhanced bladder permeability (9,17,22,31). For the IC patient, the presence of urine is responsible for inflammation and pain in addition to promoting thinning and sloughing of the urothelium and distinct changes in the muscle (21,27,30). A high proportion of IC patients show loss of chondroitin sulfate from the luminal surface of the urothelium as well as abnormalities in uroplakin, the cell adherence protein E-cadherin, and ZO-1, the molecule in the zona occludens that links cells together (9). The identification of comorbitities that appear frequently with IC has suggested that the bladder symptoms are part of a wider spectrum of symptoms denoted by chronic pelvic pain (CPP) or IC/painful bladder syndrome (IC/...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

In the absence of overt urothelial damage, chondroitinase ABC digestion of the GAG layer increases bladder permeability in ovariectomized female rats

Hurst

Gordon

Tyler

et al. 2016

American Journal of Physiology-Renal Physiology

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“…Parsons et al. suggested that cationic urinary components could potentially be cytotoxic to the urothelial cells, resulting in bladder mucosal injury 52,53 . Some dietary metabolites, medications and nutritional supplements also exert cytotoxic effects on the urothelium 26 .…”

Section: Pathophysiology Of Ic/bpsmentioning

confidence: 99%

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

et al. 2020

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Abbreviations & Acronyms BPS = bladder pain syndrome CCL2 = C-C motif ligand 2 CNS = central nervous system DMSO = dimethyl sulfoxide EAC = experimental autoimmune cystitis ESSIC = International Society for the Study of BPS FSS = functional somatic syndrome GAG = glycosaminoglycan IC = interstitial cystitis IFN-c = interferon-gamma IL = interleukin MC = mast cell NGF = nerve growth factor OVA = ovalbumin TCR = T-cell receptor TNF = tumor necrosis factor TLR = Toll-like receptor UCPPS = urological chronic pelvic pain syndrome UPK = uroplakin Upo = unpublished observation VEGF = vascular endothelial growth factor WAS = water avoidance stress Correspondence: Yoshiyuki Abstract: Interstitial cystitis/bladder pain syndrome is a debilitating condition of unknown etiology characterized by persistent pelvic pain with lower urinary tract symptoms and comprises a wide variety of potentially clinically useful phenotypes with different possible etiologies. Current clinicopathological and genomic evidence suggests that interstitial cystitis/bladder pain syndrome should be categorized by the presence or absence of Hunner lesions, rather than by clinical phenotyping based on symptomatology. The Hunner lesion subtype is a distinct inflammatory disease with proven bladder etiology characterized by epithelial denudation and enhanced immune responses frequently accompanied by clonal expansion of infiltrating B cells, with potential engagement of infection. Meanwhile, the non-Hunner lesion subtype is a noninflammatory disorder with little evidence of bladder etiology. It is potentially associated with urothelial malfunction and neurophysiological dysfunction, and frequently presents with somatic and/or psychological symptoms, that commonly result in central nervous sensitization. Animal models of autoimmune cystitis and neurogenic sensitization might serve as disease models for the Hunner lesion and non-Hunner lesion subtypes, respectively. Here, we revisit the taxonomy of interstitial cystitis/bladder pain syndrome according to current research, and discuss its potential pathophysiology and representative animal models. Categorization of interstitial cystitis/bladder pain syndrome based on cystoscopy is mandatory to design optimized treatment and research strategies for each subtype. A tailored approach that specifically targets the characteristic inflammation and epithelial denudation for the Hunner lesion subtype, or the urothelial malfunction, sensitized/altered nervous system and psychosocial problems for the non-Hunner lesion subtype, is essential for better clinical management and research progress in this complex condition.

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“…18,19 Recent studies in male and female IC patients reported that patients have more than a twofold increase in urinary cationic organic metabolites, compared with control participants, that are toxic to cultured urothelial cells. 20,21 It is proposed that these cations injure the bladder mucus barrier, and initiate the IC cascade of epithelial leak and potassium diffusion into the bladder wall. These reports were from one center, UCSD.…”

Section: Introductionmentioning

confidence: 99%

Role of urinary cations in the etiology of interstitial cystitis: A multisite study

Parsons

Argade

Evans³

et al. 2020

Int J of Urology

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Objective To determine whether patients with interstitial cystitis have elevated levels of toxic urinary cations, to identify and quantify these cationic metabolites, and to assess their cytotoxicity. Methods Isolation of cationic fraction was achieved by solid phase extraction using an Oasis MCX cartridge on urine specimens from interstitial cystitis patients and controls. C18 reverse phase high‐performance liquid chromatography was used to profile cationic metabolites, and they were quantified by the area under the peaks and normalized to creatinine. Major cationic fraction peaks were identified by reverse phase high‐performance liquid chromatography and liquid chromatography–mass spectrometry. HTB‐4 urothelial cells were used to determine the cytotoxicity of cationic fraction and of individual metabolites. Results The reverse phase high‐performance liquid chromatography analysis was carried out on cationic fraction metabolites isolated from urine samples of 70 interstitial cystitis patients and 34 controls. The mean for controls versus patients was 3.84 (standard error of the mean 0.20) versus 6.71 (0.37) mAU*min/µg creatinine, respectively (P = 0.0001). The cationic fraction cytotoxicity normalized to creatinine for controls versus patients in mean percentage was −7.79% (standard error of the mean 3.32%) versus 20.03% (standard error of the mean 2.75%; P < 0.0005). The major toxic cations were 1‐methyladenosine, 1‐methylguanine, N2,N2‐dimethylguanosine and L‐tryptophan. Conclusions These data confirm significant elevation of toxic cations in the urine of interstitial cystitis patients. These toxic cations likely represent a primary cause of interstitial cystitis, as they can injure the bladder mucus and initiate an epithelial leak.

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Role of urinary cations in the aetiology of bladder symptoms and interstitial cystitis

Cited by 29 publications

References 27 publications

In the absence of overt urothelial damage, chondroitinase ABC digestion of the GAG layer increases bladder permeability in ovariectomized female rats

In the absence of overt urothelial damage, chondroitinase ABC digestion of the GAG layer increases bladder permeability in ovariectomized female rats

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

Role of urinary cations in the etiology of interstitial cystitis: A multisite study

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