P2X7 Receptor Blockade Protects Against Acrolein-Induced Bladder Damage: A Potential New Therapeutic Approach for the Treatment of Bladder Inflammatory Diseases

Abstract

Inflammatory conditions of the urinary bladder have been shown to be associated with urothelial damage and loss of function. The purinergic P2X7 receptor has been implicated in several inflammatory conditions. The aim of this study was to investigate the role of the P2X7 receptor in acrolein-induced inflammatory damage using the porcine urinary bladder. For this purpose, an ex-vivo model of porcine urothelial damage induced by direct instillation of acrolein into the whole bladder lumen was used. To determine the role of the P2X7 receptor, the bladders were pre-incubated with a selective P2X7 receptor antagonist, A804598 (10 μM), for 1 h. The effects of the acrolein-induced urothelial damage on the bladder’s function were assessed by examining the bladder wall contractile response, structure changes, apoptosis, and oxidative stress in the bladder tissues. The acrolein treatment led to significant damage to the urothelium histology, tight junction expression, and contractile responses. Acrolein also induced apoptosis in the mucosa layer. All these acrolein-induced responses were attenuated by pre-treatment with the P2X7 receptor antagonist A804598. Acrolein also significantly induced DNA oxidation in the submucosal layer; however, the P2X7 receptor antagonism did not show any protective effect towards the acrolein-induced oxidative stress. These findings suggested that the P2X7 receptor is involved in the acrolein-induced damage to the urothelium; therefore, the P2X7 receptor antagonists may be a new therapeutic option for the treatment of bladder inflammation.

Protective Effect of Purinergic P2X7 Receptor Inhibition on Acrolein-Induced Urothelial Cell Damage

“…These changes, which are analogous to the changes seen in patients with interstitial cystitis, were inhibited by pre-treatment of urothelial cells with P2X7R antagonist, A804598. These findings are in line with our previously reported observations in our ex-vivo model of urothelial damage by direct instillation of acrolein into the whole porcine bladder lumen ( Taidi et al, 2021 ) and provide further evidence for the potential of P2X7R antagonists in the treatment of IC/PBS.…”

“…Using an ex-vivo porcine bladder model, we have recently reported that instillation of acrolein into the bladder lumen caused damage to the urothelial and suburothelial layers, along with diminished bladder contractility in response to acetylcholine stimulation. The addition of P2X7R antagonist significantly attenuated acrolein-induced damage to the bladder ( Taidi et al, 2021 ). The aim of this study was to further investigate whether the P2X7R is involved in acrolein-induced changes in urothelial barrier structure and integrity at the cellular level.…”

The Pannexin 1 Channel and the P2X7 Receptor Are in Complex Interplay to Regulate the Release of Soluble Ectonucleotidases in the Murine Bladder Lamina Propria

“…As the cytosolic concentrations of ATP are 1–5 mM [ 41 , 42 ], it is conceivable that ATP released through exocytosis or through PANX1 channels in close proximity with P2X7R can transiently reach effective concentrations to activate this receptor. Like PANX1, P2X7R plays a role in activating and sustaining inflammation and has been implicated in several inflammatory and autoimmune diseases and cancer [ 43 , 44 ], including in the inflammatory processes of animal models of cyclophosphamide or acrolein-induced cystitis [ 45 , 46 ]. It was initially proposed that activation of P2X7R permeabilizes cells to large molecules, such as nucleotides, through gradual dilation of its own channel pore [ 38 , 47 ], or via interaction with other channel-forming proteins (e.g., PANX1) [ 10 ].…”