Sphingosine Kinase 1 urothelial expression is increased in patients with neurogenic detrusor overactivity

Abstract

Objectives:To evaluate the expression of sphingosine kinase 1 (SPK1) in the bladder wall in patients with neurogenic lower urinary tract dysfunction and its association with clinical, urodynamic and pathological features.Materials and Methods:The expression of SPK1 was studied in bladder wall specimens obtained from cystectomy using immunohistochemistry in ten patients with spinal cord injury (n=8) or multiple sclerosis (n=2) with urodynamically proven neuropathic bladder dysfunction, and in controls (n=5). Inflammation and fibrosis were analysed with histological criteria and SPK1 expression was determined by individual immunohistochemical staining.Results:Significant increased SPK1 urothelial immunoreactivity was shown in patients compared to control group (p=0.03). By contrast, SPK1 immunoreactivity in patients was significantly decreased in the sub-urothelium, muscles and nerves, p=0.02; 0.01 and 0.003, respectively. Patients with neurogenic detrusor overactivity (NDO) had higher SPK1 urothelium expression than those without any DO (p=0.04).Conclusions:SPK1 is expressed in the human bladder wall, specifically the urothelium, in bladder specimens from patients with NDO. The role of SPK1 in the pathophysiology of NDO needs further elucidation.

Urothelial proliferation and regeneration after spinal cord injury

“…Importantly, changes in urothelial differentiation are likely to manifest in altered gene expression and urothelial function, as well as increased susceptibility to bacterial infections. Work to date indicates that the urothelium of patients with SCI exhibits modified expression of CDH1 (alias E-cadherin), EGFR, SPHK1 (alias sphingosine kinase 1), and TJP1 (3,10,13,21,56). We surmise that the expression of other proteins may similarly be affected, and these changes could further contribute to disrupted bladder function.…”

Modulation of lower urinary tract smooth muscle contraction and relaxation by the urothelium

“…Based on the role of the urothelium in sensing the cellular environment and releasing mediators to modify it, several investigators have explored alterations of a wide range of parameters related to the morphology and function of the urothelium (Table 2). Such investigations were reported for various species including mouse (Daly et al, 2014) (Pak et al, 2010), rat (Johansson et al, 2002a, Afiatpour et al, 2003, Liu and Daneshgari, 2006, Doyle et al, 2018 (Eika et al, 1993, Haefliger et al, 2002, Pitre et al, 2002, Murray et al, 2004, Chopra et al, 2005, Tong et al, 2006, Barendrecht et al, 2007, Andersson et al, 2008, Hanna-Mitchell et al, 2013, Coelho et al, 2015, Xiao et al, 2015 (Andersson et al, 2008), rabbit (Santarosa et al, 1994, Azadzoi et al, 1999, Azadzoi et al, 2010) and human (Lowe et al, 1997, Vaidyanathan et al, 1998, Mansfield et al, 2005, Datta et al, 2010, Kumar et al, 2010, Munoz et al, 2011, Bschleipfer et al, 2012, Kurizaki et al, 2013, Ballouhey et al, 2015, as well as in vitro with cell lines derived from human urothelium (Kang et al, 2015). They involved a range of conditions including ageing (Afiatpour et al, 2003, Mansfield et al, 2005, Daly et al, 2014, overactive bladder syndrome (OAB)/idiopathic detrusor overactivity…”

“…Sphingosine kinase human NVD increase (Ballouhey et al, 2015) Inducible NO synthase rat BOO increase (Johansson et al, 2002a) Endothelial NO synthase rat BOO decrease (Johansson et al, 2002a) Connexins rat BOO increase (Haefliger et al, 2002) bFGF, TGF rabbit BOO increase (Santarosa et al, 1994) NGF rat cystitis increase (Coelho et al, 2015) human cystitis increase (Lowe et al, 1997) DNA synthesis rat diabetes increase (Eika et al, 1993) Legends to the figures In response to these inputs, the urothelium releases a number of chemical mediators including ciliary neurotrophic factor (CNF), macrophage migration inhibitory factor (MIF), leukocyte inhibitory factor (LIF), hydrogen sulphide (H2S), urothelium-derived inhibitory factor (UDIF), and interleukins (IL). These actions of these mediators on smooth muscle can be excitatory [+], inhibitory [-] or unknown [?…”