Abstract
This study assessed the functional role of WNT genes and the association between WNT signalling cascades and fibrosis in interstitial cystitis/bladder pain syndrome (IC/BPS) patients. Twenty-five patients (3 males, 22 females; mean age 59.7 ± 10.9 years), included 7 non-Hunner-type IC (NHIC), 18 Hunner-type IC (HIC), and 5 non-IC (control) groups. The expression of sonic hedgehog, WNT gene family, and genes previously reported as biomarkers for IC/BPS were examined using RT-PCR in biopsy specimens from the mucosa and submucosa layer of the bladder. WNT2B, WNT5A, WNT10A, and WNT11 functions in the urothelium were evaluated by silencing in an HBlEpC cell line. Pelvic Pain and Urgency/Frequency Patient Symptom Scale scores, O’Leary-Sant Symptom and Problem Index scores, and Visual Analogue Scores did not differ between the NHIC and HIC groups. However, HIC patients had significantly shorter symptom duration (30.9 vs 70.8 months, p = 0.046), higher daily urinary frequency (16.1 versus 8.5 times, p = 0.006), and smaller bladder capacity (208.6 versus 361.4 ml, p = 0.006) than NHIC patients. Overall WNT gene expression was lower in NHIC than HIC patients. Bladder epithelial tissues from HIC patients were characterised by the downregulation of WNT11. Silencing of WNT11, WNT2B, WNT5A, and WNT10A in HBlEpCs resulted in fibrotic changes, indicated by fibrotic morphology, increased fibrosis-related gene expression, and nuclear localisation of phosphorylated SMAD2, and increased vimentin and fibronectin levels. Downregulation of WNT11 results in fibrotic changes of bladder epithelial cells and is associated with the pathogenesis and differential diagnosis of NHIC. Decreased expression of WNT11 is a potential biomarker for predicting NHIC.
Highlights
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a distressing, chronic bladder disorder characterised by urinary frequency, urgency, nocturia, and pelvic pain without bacterial infection or an identifiable pathologic cause[1]
We observed that downregulation of WNT11 is associated with bladder tissue fibrosis in non-Hunner-type IC (NHIC) patients than in Hunner-type IC (HIC) patients
Higher WNT2B and WNT5A expression was observed in HIC patients than in NHIC patients
Summary
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a distressing, chronic bladder disorder characterised by urinary frequency, urgency, nocturia, and pelvic pain without bacterial infection or an identifiable pathologic cause[1]. Data are represented as a dot plot of mean ± SEM [n = 6 for non-IC; n = 11 for non-Hunner-type IC (NHIC) and n = 19 for Hunner lesions in Hunner-type IC (HIC); *p < 0.05 using one-way ANOVA analysis with a Bonferroni post-hoc test]. Several theories including developmental defects in the Tamm-Horsfall protein, potassium sensitivity theory, and autoimmunity have been posited Their detail mechanisms remain unclear[6,7]. HIC is currently treated using transurethral resection and PCR analysis of the genes involved in SHH (a) and WNT (b) pathways in the bladder tissues of the indicated patient groups. Data are represented as a dot plot of mean ± SEM [n = 6 for non-IC; n = 11 for NHIC and 19 for HIC patient groups; *p < 0.05 by one-way ANOVA analysis with a Bonferroni post-hoc test]
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