A Role for the Hedgehog Effector Gli1 in Mediating Stent-induced Ureteral Smooth Muscle Dysfunction and Aperistalsis

Abstract

To better understand the effects of double J stenting on ureteral physiology and function. In total, 24 pigs were stented cystoscopically unilaterally for 48 hours, 1, 2, 4, and 7 weeks. Controls consisted of un-stented animals (n = 4) or the contralateral un-stented ureter in pigs. Ureters were harvested and tested in tissue baths to evaluate their contractility. Ureteral inflammation and expression of Sonic Hedgehog (Shh) and the transcriptional activator Gli1 (the downstream target of active Hedgehog signaling) were assessed histologically and by immunohistochemistry, respectively. Indwelling ureteral stents were found to abolish normal ureteral function in all animals. Specifically, ureteral smooth muscle (SM) activity was significantly diminished within 48 hours after stenting and persisted at the 1-week time point. Furthermore, ureteral SM dysfunction was associated with increasing ureteral dilation due to the indwelling stent. Simultaneously, we observed a loss of Gli1 expression in SM cells, with a concomitant increase in ureteral inflammation. Expression of Shh was restricted to the urothelium and was not different between controls, stented, and contralateral ureters. Stent-induced aperistalsis was associated with diminished SM contractility, increased tissue inflammation, and reduced Gli1 expression in ureteral SM cells, independent of Shh expression. The present study is the first to show that indwelling stents negatively affect ureteral SM activity and identify a role for specific molecular mechanisms involved.