Login to Access Video or Poster Abstract: MP23-20
Sources of Funding: NIDDK: R01DK103534 (PI - Purves)

Introduction

Bladder outlet obstruction (BOO) is a common condition resulting from benign prostatic hyperplasia, neurologic pathology, organ prolapse, etc. Long-term, obstruction is well-established to evoke denervation in the bladder which causes the detrusor to become hypocontractile, leading to inefficient bladder emptying and consequent infections, continence issues or even renal failure. Recently, considerable attention has been paid to a role for inflammation in bladder deterioration during BOO and we have shown a central role for the NLRP3 inflammasome in triggering this inflammation. In the present study we explore a possible connection between this NLRP3-induced inflammation and bladder denervation.

Methods

Rats were divided into 5 groups: 1) Control, 2) SHAM operated, 3) BOO+Vehicle, 4) BOO+Glyburide (Gly, NLRP3 inhibitor; 10 mg/kg, p.o.), 5) BOO+Anakinra (Ana, IL-1 receptor antagonist; 25 mg/kg, i.p.). BOO is constructed in female rats by inserting a 1 mm outer diameter transurethral catheter, tying a silk ligature around the urethra and removing the catheter. Medications were administered pre-operatively and once daily. At 12 days animals were sacrificed and the bladders processed for histological analysis. Transverse sections were stained for PGP9.5 expression (pan-neuronal marker) using standard immunohistochemistry techniques. Entire sections were scanned and the area of individual neurons designated as well as total bladder area (exclusive of the urothelia and lumen). The number of neurons and respective areas were used to calculate nerve density.

Results

Denervation in the bladder wall during BOO was highly significant, as measured by nerve density. This effect was attenuated by either preventing NLRP3 activation with Gly or blocking the action of IL-1β at its receptor by treatment with Ana, clearly indicating a role for NLRP3/IL-1β in bladder denervation during BOO. The effect was also apparent with the total number of nerves despite considerable changes in bladder wall area (increased in BOO, maintained by Gly or Ana).

Conclusions

NLRP3/IL-1β-induced inflammation contributes to bladder denervation during BOO and blocking this pathway, either by preventing NLRP3 activation or inhibiting the action of IL-1β, diminishes nerve loss.

Funding

NIDDK: R01DK103534 (PI - Purves)