Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes

Abstract

Diabetic bladder dysfunction (DBD) is common and affects 80% of diabetic patients. However, the molecular mechanisms underlying DBD remain elusive because of a lack of appropriate animal models. We demonstrate DBD in a mouse model that harbors hepatic-specific insulin receptor substrate 1 and 2 deletions (double knockout [DKO]), which develops type 2 diabetes. Bladders of DKO animals exhibited detrusor overactivity at an early stage: increased frequency of nonvoiding contractions during bladder filling, decreased voided volume, and dispersed urine spot patterns. In contrast, older animals with diabetes exhibited detrusor hypoactivity, findings consistent with clinical features of diabetes in humans. The tumor necrosis factor (TNF) superfamily genes were upregulated in DKO bladders. In particular, TNF-α was upregulated in serum and in bladder smooth muscle tissue. TNF-α augmented the contraction of primary cultured bladder smooth muscle cells through upregulating Rho kinase activity and phosphorylating myosin light chain. Systemic treatment of DKO animals with soluble TNF receptor 1 (TNFRI) prevented upregulation of Rho A signaling and reversed the bladder dysfunction, without affecting hyperglycemia. TNFRI combined with the antidiabetic agent, metformin, improved DBD beyond that achieved with metformin alone, suggesting that therapies targeting TNF-α may have utility in reversing the secondary urologic complications of type 2 diabetes.

Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction

“…These findings are supported by a previous study implicating this cytokine in developing bladder dysfunction in an animal model of type 2 diabetes, which is associated with bladder hypertrophy and overactivity (31). Similarly, studies using detrusor smooth muscle cells showed that TNF-α and IL-1β induced secretion of IL-8 and IL-6 (32), in line with our data in BOO patients.…”

Stem Cell Therapy: Current Applications and Potential for Urology

“…Proinflammatory cytokines are essential in stimulating the angiogenic, lineage-specific differentiation, proliferative, and immunomodulatory functions of stem cells. Interleukin (IL) 1α and β, tumor necrotic factor (TNF) α, and interferon are examples of proinflammatory markers that play roles in kidney fibrosis, cancers, bladder obstruction, and other urologic diseases [84][85][86][87]. Recent studies in our lab showed that hypoxia treatment of normal bladder smooth muscle cells results in a time-dependent increase in endogenous TNFα levels.…”

Chronic treatment with resveratrol improves overactive bladder in obese mice via antioxidant activity

“…Overactive bladder is often associated with detrusor overactivity, an urodynamic observation characterized by involuntary detrusor contractions during the filling phase, which may be spontaneous or provoked (Irwin et al, 2006). Obese animals exhibit cystometric alterations such as increases in the frequency of voiding and non-voiding contractions, along with in vitro detrusor overactivity Rahman et al, 2007;Wang et al, 2012). Urethral smooth muscle dysfunction due to impairment of the nitric oxide signal transduction also occurs in conditions of obesity .…”

“…Obesity has been described as a low-grade chronic inflammation associated with cardiovascular diseases and diabetes along with premature mortality (Apostolopoulos et al, 2016;Wang et al, 2012). Clinical studies have also implicated obesity as a major contributing factor for the lower urinary tract symptoms (Steers, 2009), which comprises storage, voiding or post micturition symptoms (Irwin et al, 2011).…”