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

• Applicant: Dr. Alina Reicherz
• Subject Area: Reproductive Medicine, Urology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 447617010

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.

• DFG Programme: WBP Fellowship
• International Connection: Canada
• Host: Professor Dr. Dirk Lange, Ph.D.