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Gender-dependent bladder response to one-day bladder outlet obstruction

Published:January 02, 2021DOI:https://doi.org/10.1016/j.jpurol.2020.12.026

      Summary

      Background

      Development of bladder fibrosis, loss of compliance, and voiding dysfunction are among the severe consequences of various lower urinary conditions, for example, bladder outlet obstruction (BOO), neurogenic bladder, and radiotherapy to the pelvic area. The bladder remodelling results in significant changes in bladder function and architecture, and may ultimately be deleterious for kidney function. The molecular signals underlying pathologic bladder remodelling, as well as the impact of gender, remain poorly understood.

      Objective

      To investigate the bladder remodelling after one day BOO, whether the remodelling is different between different bladder sections, and whether genders may affect the remodelling.

      Study design

      Thirty male and 30 female C57BL/6NRj mice were randomly divided into Control, Sham and BOO groups with ten mice per group. A 24-h total urethral obstruction was performed at the proximal urethra. Histological changes were observed via H&E, trichrome and immunohistochemistry staining. Harvested bladders were divided into upper and lower sections for analysis. Protein and gene expression were detected by Western blotting and qPCR.

      Results

      No significant changes in bladder wall thickness were observed following BOO, while increased bladder mass after BOO was found in female mice only. We detected FN and ⍺-SMA upregulation in the male upper bladder segment. Female BOO mice bladders showed increased α-SMA expression in both bladder segments, but no difference of FN was observed in either bladder segments. BOO-induced upregulation of TGF-β and Gremlin were detected in both male and female bladders, while downregulation of BMP-7 was detected only in male bladders. Furthermore, phosphorylation of both SMAD2/3 and SMAD1/5/9 were increased in male bladders following BOO, whereas female mice exhibited increased pSMAD2/3 in the upper and increased pSMAD1/5/9 in the lower bladder segment.

      Conclusions

      Summary Figure
      Graphical AbstractMice bladder wall thickness and bladder wet weight changes after acute total bladder outlet obstruction. A significant increase of bladder weight was detected in female mice compared to control (P < 0.001) and sham (P = 0.002), while bladder wall thickness in the female obstruction group was similar to those in the control and sham groups. Bars are mean ± SEM. No significant differences in bladder wall thickness or bladder weight were found in the male mice. Each group, n = 3–4. Statistical analysis was performed using One-way analysis of variance (ANOVA). ∗p < 0.05.

      Keywords

      Abbreviations:

      ALK (activin receptor-like kinase), BMP (bone morphogenetic protein), BSA (bovine serum albumin), BOO (bladder outlet obstruction), EMT (epithelial-to-mesenchymal transition), ECM (extracellular matrix), FN (fibronectin), H&E (Hematoxylin and Eosin staining), IHC (Immunohistochemistry), PBS (phosphate buffered saline), RIPA (radioimmunoprecipitation assay), PCR (polymerase chain reaction), TGF-β (transforming growth factor-beta), α-SMA (alfa-smooth muscle actin)
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