Role of mPGES-1 inhibition on regeneration of ureteral function in a murine model of obstructive uropathy

介绍输尿管结石、肿瘤、UPJ等引起的输尿管梗阻，可引起疼痛、感染和潜在的肾损害。输尿管运动和膀胱扩张通常将尿团从肾脏推进膀胱。输尿管梗阻引起肾盂破裂和肾积水。使用小鼠或猪输尿管梗阻模型的研究观察到由考克斯-2/mPGES-1/PGE 2级联触发的肾积水和炎症机制。肠梗阻后运动的研究显示mPGES-1抑制对长期运动的有希望的作用。我们试图确定考克斯-2和mPGES-1抑制在输尿管梗阻后输尿管再生过程中的作用。特别感兴趣的事项是1。 监测植物再生2.） 尿道再生后尿道上皮中考克斯-2和mPGES-1表达的持续机会3.） 对尿液中PGE 2浓度的影响4.） 方法将30只小鼠/组建立单侧输尿管梗阻24 h、7 d和14 d。在阻塞期间，每组15只小鼠接受mPGES-1-抑制剂CAY 10526，15只小鼠接受考克斯-2-抑制剂NS-398，15只对照接受盐水。在输尿管功能再生后，我们通过蛋白质印迹和免疫组织化学检测梗阻和通畅输尿管中mPGES-1和考克斯-2的表达。在梗阻之前、期间和之后监测蠕动和尿液中的PGE 2浓度。将对输尿管和肾盂进行组织学分析，以确定持续影响。目的本研究旨在寻找抑制梗阻性炎症引起输尿管功能障碍的途径。确定这种机制，将允许开发新的治疗途径。考克斯-2-和mPGES-1-抑制剂可能加速再生，从而减少输尿管梗阻的主要并发症输尿管狭窄的损失。

IntroductionUreteral obstruction caused by ureteral stone, tumors, UPJ e.g. and may cause pain and lead to infection and potential kidney damage. Ureteral motility and peristalsis normally propel boluses of urine from the kidney to the bladder. Ureteral obstruction causes a disruption of peristalsis and hydronephrosis. Studies using a mouse or porcine model of ureteral obstruction observed hydronephrosis and inflammatory mechanisms triggered by the COX-2/mPGES-1/PGE2 cascade. Studies on motility after bowel obstruction show promising effects of mPGES-1-inhibition on long term motility. ObjectiveWe seek to determine the role of COX-2 and mPGES-1 inhibition in the process of ureteral regeneration after ureteral obstruction. Especial matter of interest are1.) Monitoring the regeneration of peristalsis2.) Lasting chances in the COX-2- and mPGES-1-expression in the urothelium after regeneration of peristalsis 3.) Impacts on the PGE2 concentration in the urine4.) Lasting histomorphologic changes in the ureter e.g. fibrosisMethodsUnilateral ureteral obstruction will be created for 24 h, 7 d and 14 days in 30 mice per group. 15 mice per group will receive the mPGES-1-inhibitor CAY10526, 15 mice the COX-2-inhibitor NS-398 and 15 controls received saline during obstruction. After regeneration of ureteral function we determine mPGES-1 and COX-2 expression in the obstructed and unobstructed ureters by western blot and immunohistochemistry. Peristalsis and PGE2-concentration in the urine will be monitored before, during and after obstruction. Histological analysis of the ureter and renal pelvis will be performed to identify lasting effects. Tissue of 10 mice will be examined after sham procedure.AimThe present study might identify a pathway that inhibits the obstruction induced inflammation causing ureteral dysfunction. Identifying this mechanism, would allow the development of novel therapeutic avenues. COX-2- and mPGES-1-inhibitors might accelerate regeneration and thus reduce the loss of ureteral peristalsis, a major complication of ureteral obstruction.