Functional and Molecular Changes of the Bladder in Rats with Crushing Injury of Nerve Bundles from Major Pelvic Ganglion to the Bladder: Role of RhoA/Rho Kinase Pathway

Abstract

Voiding dysfunction is a common complication after radical pelvic surgery. To reduce this complication, nerve-sparing radical pelvic surgery was introduced. However, several patients experienced voiding difficulty despite nerve-sparing radical pelvic surgery. Thus, we investigated the functional and molecular changes of the bladder in rats, which demonstrated voiding dysfunction induced by nerve damage during nerve-sparing radical pelvic surgery. Male rats were used and assigned to normal, sham-operated, and bilateral crushing nerve bundles from major pelvic ganglion (MPG) to bladder group. After one, two, and four-week crushing injury, significantly decreased contractile response and increased connective tissue of the detrusor were observed and these results were reliable findings with voiding difficulty following nerve-sparing radical pelvic surgery. After crushing injury, significantly increased M2 muscarinic receptor expression was observed and this might be regarded as the compensatory response. However, M3 muscarinic receptor expression was not significantly changed. The expression of RhoA, ROCK-α, and ROCK-β was significantly increased after one, two, and four-week crushing injury. From these results, the down-regulation of RhoA/Rho kinase pathway might lead to the decreased bladder contractility after crushing injury of nerve bundles from MPG to the bladder despite of the compensated up-regulation of M2 muscarinic receptor.

Impaired contraction and decreased detrusor innervation in a female rat model of pelvic neuropraxia

“…Contraction at later time points successively increased to closely approximate sham contraction by 30 days post-nerve crush. In male rats, decreased detrusor contraction to both low and high frequency EFS was evident 1, 2 and 4 weeks post-injury [24]. These findings suggest a decline in available bladder cholinergic nerve activation following BPNI which is also supported by the decrease in markers specific to cholinergic nerve terminals 7–30 days following BPNI.…”

“…A comparable switch following BPNI may explain increased carbachol contractile response during periods of decreased M3 receptor expression. In contrast, a male rat model of cavernous nerve crush injury found increased M2 and no change in M3 protein expression at 1, 2 and 4 weeks post-crush [24]. Further studies are required to elucidate the role of M2 versus M3 receptor following BPNI.…”

“…Further studies are required to elucidate the role of M2 versus M3 receptor following BPNI. The role of other signaling pathways in the bladder should also be assessed in this RH model as changes to purinergic signaling or downstream pathways such as rho-kinase may also lead to increased contraction early post-injury [24,25]. Overall, it appears that the bladder is compensating for the decreased innervation caused by nerve injury by increasing its ability to contract to cholinergic agonist in order to maintain the ability to void.…”

Amniotic Fluid Stem Cells Improve Rat Bladder Dysfunction After Pelvic Nerve Transection

“…Our results showed that bladder weight increased after PNT but improved after hAFSCs transplantation. Bilateral pelvic nerve crush could cause detrusor muscle hypertrophy and increase collagen deposition 12,13 , and bilateral PNT caused bladder wall muscle hyperplasia and hypertrophy with increased bladder weight in rats 14 . However, Kwon et al 15 reported that unilateral PNT caused no change of bladder weight in rats treated with muscle-derived stem cells and sham operation and also no change in normal controls.…”

Pathophysiology of the underactive bladder

“…There have been several published studies reported as a UAB model by using pelvic nerve crash- or cryoinjury (unilaterally or bilaterally) [ 92 93 94 95 96 ], in which detrusor contractility was remarkably impaired. In case of bilateral pelvic nerve injury by complete resection, the animals showed severe nervous dysfunctions, which were resemble to the situation with SCI [ 95 ].…”