https://ror.org/04pge2a40 Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China.
Life Sci Alliance. 2024 Nov 22;8(2). doi: 10.26508/lsa.202402957. Print 2025 Feb.
Interstitial cystitis/bladder pain syndrome (IC/BPS) represents a chronic, aseptic inflammatory bladder condition with an unclear etiology and few therapeutic options. A composite barrier structure composed of the uroepithelium and glycosaminoglycan layer forms on the bladder's inner surface to block urine and other harmful substances. Dysfunction of this barrier may initiate the pathogenesis of IC/BPS. Sphingosine-1-phosphate (S1P) plays a crucial role in forming tight junctions. Perfusion of S1P into the bladder restored uroepithelial tight junctions in mice with cyclophosphamide-induced acute cystitis and ameliorated symptoms of the lower urinary tract. Mice lacking sphingosine kinase 1 (SHPK1) exhibited more severe bladder injuries and dysfunction. Concurrent in vitro experiments elucidated S1P's protective effects and its role as a primary messenger through SPHK1 and S1P receptor 1 (S1PR1) knockdown. This study identifies a novel mechanism whereby S1P binding to S1PR1 activates the PPAR-α pathway, thereby enhancing cholesterol transport and restoring tight junctions between uroepithelial cells. These findings elucidate the regulatory role of S1P in the bladder epithelial barrier and highlight a promising therapeutic target for IC/BPS.
间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是一种慢性、无菌性炎症性膀胱疾病，其病因不明，治疗选择有限。由尿路上皮和糖胺聚糖层组成的复合屏障结构在膀胱内表面形成，以阻止尿液和其他有害物质进入。该屏障的功能障碍可能引发 IC/BPS 的发病机制。鞘氨醇-1-磷酸（S1P）在形成紧密连接中起着至关重要的作用。将 S1P 灌注到患有环磷酰胺诱导的急性膀胱炎的小鼠的膀胱中，恢复了尿路上皮的紧密连接，并改善了下尿路症状。缺乏鞘氨醇激酶 1（SHPK1）的小鼠表现出更严重的膀胱损伤和功能障碍。同时进行的体外实验阐明了 S1P 通过 SPHK1 和 S1P 受体 1（S1PR1）敲低发挥其保护作用及其作为主要信使的作用。这项研究确定了一种新的机制，即 S1P 与 S1PR1 结合激活 PPAR-α 途径，从而增强胆固醇转运并恢复尿路上皮细胞之间的紧密连接。这些发现阐明了 S1P 在膀胱上皮屏障中的调节作用，并突出了 IC/BPS 的一个有前途的治疗靶点。
