PACAP/PAC1 regulation in cystitis rats: induction of bladder inflammation cascade leading to bladder dysfunction

Front Immunol. 2024 Nov 28:15:1413078. doi: 10.3389/fimmu.2024.1413078. eCollection 2024.

Abstract

Introduction: Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic and debilitating condition marked by bladder pain, urinary urgency, and frequency. The pathophysiology of IC/BPS remains poorly understood, with limited therapeutic options available. The role of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its receptor PAC1 in IC/BPS has not been thoroughly investigated, despite their potential involvement in inflammation and sensory dysfunction. This study aims to examine the expression and functional role of the PACAP/PAC1 signaling pathway in the pathogenesis of IC/BPS.

Methods: Bladder tissue samples from IC/BPS patients and a rat model of cystitis were analyzed to evaluate PACAP and PAC1 expression. Transcriptomic analysis, immunohistochemistry, and bladder function assays were employed to assess the correlation between PACAP/PAC1 activation, bladder inflammation, and sensory dysfunction. Additionally, modulation of the PACAP/PAC1 pathway was tested in rats to determine its effects on bladder inflammation and function.

Results: Our results demonstrate significant upregulation of PACAP and PAC1 in both human bladder tissues from IC/BPS patients and in the rat cystitis model. This upregulation was associated with increased bladder inflammation and sensory dysfunction. Intervention with PACAP/PAC1 pathway modulation in rats resulted in a marked reduction in bladder inflammation and improvement in bladder function, suggesting the pathway's pivotal role in disease progression.

Discussion: The findings provide compelling evidence that the PACAP/PAC1 pathway is involved in the inflammatory and sensory changes observed in IC/BPS. By targeting this signaling pathway, we may offer a novel therapeutic approach to mitigate the symptoms of IC/BPS. This study enhances our understanding of the molecular mechanisms driving IC/BPS and opens avenues for the development of targeted treatments.

Keywords: PAC1 receptor; PACAP; bladder inflammation; bladder pain syndrome; interstitial cystitis.

MeSH terms

  • Animals
  • Cystitis / immunology
  • Cystitis / metabolism
  • Cystitis, Interstitial* / immunology
  • Cystitis, Interstitial* / metabolism
  • Cystitis, Interstitial* / pathology
  • Disease Models, Animal*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pituitary Adenylate Cyclase-Activating Polypeptide* / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I* / genetics
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I* / metabolism
  • Signal Transduction
  • Urinary Bladder* / metabolism
  • Urinary Bladder* / pathology

Substances

  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National Natural Science Foundation of China (Grant No.81970660); Beijing Natural Science Foundation (7242153) and Research and Development Fund of Peking University People’s Hospital (2147000692).