The internal surface of the bladder is lined by the urothelium, a stratified epithelium that forms an impermeable barrier to water and urine constituents. Abnormalities in the urothelial barrier have been described in certain forms of cystitis and were hypothesized to contribute to irritative voiding symptoms and pain by allowing the permeation of urinary K⁺ into suburothelial tissues, which then alters afferent signaling and smooth muscle function. Here, we examined the mechanisms underlying organ hyperactivity and pain in a model of cystitis caused by adenoviral-mediated expression of claudin-2 (Cldn2), a tight junction protein that forms paracellular pores and increases urothelial permeability. We found that in the presence of a leaky urothelium, intravesical K⁺ sensitizes bladder afferents and enhances their response to distension. Notably, dietary K⁺ restriction, a maneuver that reduces urinary K⁺, prevented the development of pelvic allodynia and inflammation seen in rats expressing Cldn2. Most importantly, intravesical K⁺ causes and is required to maintain bladder hyperactivity in rats with increased urothelial permeability. Our study demonstrates that in the face of a leaky urothelium, urinary K⁺ is the main determinant of afferent hyperexcitability, organ hyperactivity and pain. These findings support the notion that voiding symptoms and pain seen in forms of cystitis that coexist with urothelial barrier dysfunction could be alleviated by cutting urinary K⁺ levels.

膀胱的内表面衬有尿路上皮，尿路上皮是一种分层上皮，对水和尿液成分形成不可渗透的屏障。在某些形式的膀胱炎中已经描述了尿路上皮屏障的异常，并且推测尿​​路上皮屏障的异常通过允许尿K ⁺渗透到尿路上皮下组织中而导致刺激性排尿症状和疼痛，从而改变传入信号传导和平滑肌功能。在这里，我们研究了由腺病毒介导的 Cldn2 (Cldn2) 表达引起的膀胱炎模型中器官过度活跃和疼痛的机制，Cldn2 是一种紧密连接蛋白，可形成细胞旁孔并增加尿路上皮通透性。我们发现，在尿路上皮渗漏的情况下，膀胱内注射 K ⁺可使膀胱传入神经敏感并增强其对扩张的反应。值得注意的是，饮食 K ⁺限制（一种减少尿 K ⁺的方法）可防止表达 Cldn2 的大鼠出现骨盆异常疼痛和炎症。最重要的是，膀胱内注射 K ⁺会导致尿路上皮通透性增加的大鼠膀胱过度活跃，并且是维持膀胱过度活跃所必需的。我们的研究表明，面对尿路上皮渗漏，尿 K ⁺是传入神经过度兴奋、器官过度活跃和疼痛的主要决定因素。这些发现支持这样的观点：与尿路上皮屏障功能障碍共存的膀胱炎形式的排尿症状和疼痛可以通过降低尿 K ⁺水平来缓解。