Molecular Characterization of Non-Neurogenic and Neurogenic Lower Urinary Tract Dysfunction (LUTD) in SCI-Induced and Partial Bladder Outlet Obstruction Mouse Models

Abstract

We examined bladder function following spinal cord injury (SCI) by repeated urodynamic investigation (UDI), including external urethral sphincter (EUS) electromyography (EMG) in awake restrained mice and correlated micturition parameters to gene expression and morphological changes in the bladder. A partial bladder outlet obstruction (pBOO) model was used for comparison to elucidate both the common and specific features of obstructive and neurogenic lower urinary tract dysfunction (LUTD). Thirty female C57Bl/6J mice in each group received an implanted bladder catheter with additional electrodes placed next to the EUS in the SCI group. UDI assessments were performed weekly for 7 weeks (pBOO group) or 8 weeks (SCI group), after which bladders were harvested for histological and transcriptome analysis. SCI mice developed detrusor sphincter dyssynergia (DSD) one week after injury with high-pressure oscillations and a significantly increased maximal bladder pressure Pmax and were unable to void spontaneously during the whole observation period. They showed an increased bladder-to-bodyweight ratio, bladder fibrosis, and transcriptome changes indicative of extracellular matrix remodeling and alterations of neuronal signaling and muscle contraction. In contrast, pBOO led to a significantly increased Pmax after one week, which normalized at later time points. Increased bladder-to-bodyweight ratio and pronounced gene expression changes involving immune and inflammatory pathways were observed 7 weeks after pBOO. Comparative transcriptome analysis of SCI and pBOO bladders revealed the activation of Wnt and TGF-beta signaling in both the neurogenic and obstructive LUTD and highlighted FGF2 as a major upregulated transcription factor during organ remodeling. We conclude that SCI-induced DSD in mice leads to profound changes in neuronal signaling and muscle contractility, leading to bladder fibrosis. In a similar time frame, significant bladder remodeling following pBOO allowed for functional compensation, preserving normal micturition parameters.

Expression profiles of circular RNAs and interaction networks of competing endogenous RNAs in neurogenic bladder of rats following suprasacral spinal cord injury

“…A recent study demonstrated that mice exhibited a series of immune-inflammatory reactions in bladder tissue following SCI, including cytokine-mediated signaling and production of interleukin-6. Furthermore, transcriptomic sequencing confirmed the upregulation of genes involved in immune response (CXCL13, SYK, and CCR7) and inflammation (CCR2, CX3CL1, and TREM2) ( Von Siebenthal et al, 2023 ). The KEGG analysis also revealed that circRNAs in NB tissue linked to SSCI were significantly enriched in pathways, such as the “IL-17 signaling pathway”, the “TGF-beta signaling pathway”, the “cAMP signaling pathway”, the “PI3K-Akt signaling pathway”, and the “MAPK signaling pathway”.…”

Clinical characteristics and molecular mechanisms underlying bladder cancer in individuals with spinal cord injury: a systematic review

“…This method may be used to reduce the possibility of long-term indwelling urinary catheters. Von Siebenthal et al [25] compared bladder function in the SCI (neurogenic) and bladder outlet obstruction (obstructive) mice by repeated urodynamic examination. This study found that the SCI group had dysfunctional bladder detrusor and sphincter and significantly increased bladder pressure 1 week after injury, and the bladder gradually developed fibrosis throughout the process.…”

Integrated omics analysis unveils a DNA damage response to neurogenic injury

“…Characteristic changes include bladder wall thickening as a result of cellular hypertrophy and hyperplasia [4], as well as enhanced deposition and turnover of extracellular matrix (ECM) leading to fibrosis [5, 6]. With the advent of genome-wide expression profiling, several groups have begun to characterize the molecular landscape that underlies the response of the bladder to spinal cord damage in animal models [7–10] and in smooth muscle cells isolated from human bladder biopsies [11, 12]. In addition to verification of altered expression of ECM proteins and regulators, microarray-based expression profiling of bladder tissue from spinal cord injured rats also provided important insights into additional drivers of neurogenic bladder pathophysiology including the pro-fibrotic regulator TGFβ1 and pro-inflammatory mediators such as IL1β and S100A8/A9 [7, 8].…”