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

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.

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.

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.

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.