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

输尿管梗阻由输尿管结石、肿瘤、UPJ等引起，可引起疼痛、感染和潜在的肾脏损害。输尿管的运动和蠕动通常推动尿液从肾脏到膀胱。输尿管梗阻导致肠蠕动中断和肾积水。通过小鼠或猪输尿管梗阻模型的研究，观察到COX-2/mPGES-1/PGE2级联引发的肾积水和炎症机制。对肠梗阻后运动的研究显示，抑制mpges -1对长期运动有很好的影响。目的探讨COX-2和mPGES-1抑制在输尿管梗阻后输尿管再生过程中的作用。我特别感兴趣的是……监测肠蠕动的再生肠蠕动再生后尿路上皮中COX-2-和mpges -1表达的持续变化对尿中PGE2浓度的影响方法每组30只小鼠，分别制造输尿管单侧梗阻24 h、7 d和14 d。每组15只小鼠接受mpges -1抑制剂CAY10526, 15只小鼠接受cox -2抑制剂NS-398, 15只对照组在梗阻期间接受生理盐水。输尿管功能再生后，采用western blot和免疫组化方法检测阻滞输尿管和通畅输尿管中mPGES-1和COX-2的表达。在梗阻之前、期间和之后监测尿中的蠕动和pge2浓度。输尿管和肾盂的组织学分析将被执行，以确定持久的影响。假手术后对10只小鼠进行组织检查。目的本研究可能找到抑制梗阻性炎症引起输尿管功能障碍的途径。确定这一机制，将有助于开发新的治疗途径。COX-2-和mpges -1抑制剂可能加速再生，从而减少输尿管蠕动的丧失，输尿管蠕动是输尿管梗阻的主要并发症。

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.