Weight loss surgery improves the metabolic status in an obese rat model but does not affect bladder fibrosis associated with high fat diet feeding.

BACKGROUND: Bladder dysfunction has one of the highest prevalences as a comorbidity of obesity in industrialized countries. The aetiopathogenesis of obesity-associated bladder dysfunction is still obscure, but there is growing evidence that general metabolic changes in obese patients may be in part responsible. As demonstrated recently, high fat diet (HFD) significantly alters the protein expression in the urinary bladder, activates multiple signalling pathways associated with cell survival and inflammation and ultimately provokes bladder fibrosis in an obese rat model. The study aimed to elucidate the role of matrix metalloproteases (MMPs) and their specific tissue inhibitors of metalloproteases (TIMPs) in obesity-related bladder extracellular matrix (ECM) remodelling and the effect of weight loss surgery via sleeve gastrectomy (SG) on phenotype and molecular parameters. METHODS: Twenty-four male Sprague-Dawley rats were used for (i) characterization of the HFD phenotype and (ii) evaluation of alterations following SG. Metabolic status, the degree of bladder fibrosis and tissue expression and activity of MMP2, MMP9, MMP14, TIMP1 and TIMP2 were analysed by immunohistochemistry, enzyme-linked immunosorbent assay and activity assays. Statistical differences were calculated by analysis of variance or independent Student's t-test. A P-value <0.05 was considered statistically significant. RESULTS: In HFD rats, we found significant alterations in lipid metabolism, fat mass, free fatty acid profile, insulin resistance and inflammatory markers. Voided volume was significantly decreased, and bladder showed marked fibrosis. MMPs and TIMPs were differentially regulated depending on animal status (controls, chow diet, HFD, and SG- and sham-operated animals) in both urothelium and detrusor smooth muscle. Although animal weight and most metabolic parameters were positively affected by SG, bladder fibrosis persisted. The limitations of this study were 1 month follow-up and lack of direct measurement of bladder function. CONCLUSIONS: Early diagnosis of the bladder dysfunction associated with obesity is essential to allow targeted early intervention, that is, before manifestation of potentially irreversible ECM fibrotic alterations.

[Lipopolysaccharide-mediated regulation of interleukin-6 in cultured human detrusor smooth muscle cells]. / Regulation von Interleukin-6 durch Lipopolysaccharid-Stimulation in kultivierten humanen Detrusormyozyten.

BACKGROUND: Interleukin-6 (IL-6) is a pleiotropic cytokine which shows elevated plasma and urine levels in cancer and inflammatory diseases of the urinary tract. The aim of the study is to define IL-6 target gene regulation in cultivated human detrusor smooth muscle cells. PATIENTS AND METHODS: The expression of IL-6 and IL-6R (gp80, gp130) was studied by confocal immunofluorescence, rtPCR and Western blotting. Lipopolysaccharide (LPS) stimulation experiments were conducted in smooth muscle cell cultures derived from bladder biopsies of four male tumor patients. RESULTS: IL-6 and IL-6R expression was found in urothelium, lamina propria and detrusor cells. LPS stimulation evoked a time-dependent synthesis and/or release of IL-6, IL-6R and STAT3. CONCLUSIONS: Our results favor the notion that IL-6 can stimulate various cells of the human urinary bladder. Both detrusor cells and urothelium can serve as a source of elevated IL-6 levels. Finding genes regulated by IL-6 could be of great value for new therapeutical approaches in cancer and chronic inflammation of the lower urinary tract.

[Structure and function of suburothelial myofibroblasts in the human urinary bladder under normal and pathological conditions]. / Struktur und Funktion der suburothelialen Myofibroblasten in der humanen Harnblase unter normalen und pathologischen Bedingungen.

BACKGROUND: Myofibroblasts play a pivotal role in numerous pathological alterations. Clarification of the structure and function and of the cellular plasticity of this cell type in the bladder may lead to new insights into the pathogenesis of lower urinary tract disorders. PATIENTS AND METHODS: Bladder biopsies from patients with bladder carcinoma and interstitial cystitis were used to analyse the morphology and receptor expression using confocal immunofluorescence and electron microscopy. Cytokine effects and coupling behavior were tested in cultured myofibroblasts and detrusor smooth muscle cells. RESULTS: Myofibroblasts are in close contact with the suburothelial capillary network. They express Cx43 and form functional syncytia. The expression of muscarinic and purinergic receptors is highly variable. Dye coupling experiments showed differences to detrusor myocytes. CONCLUSIONS: Upregulation of smooth muscle cell alpha-actin and/or transdifferentiation into smooth muscle cells may contribute to the etiology of urge incontinence. A multi-step model is presented as a working hypothesis.

[New methods of patient selection for improved anticholinergic therapy]. / Neue Verfahren der optimalen Patientenselektion für die anticholinerge Therapie.

BACKGROUND: M3-specific inhibitors are currently preferred for anticholinergic therapy of OAB. However, not all of the patients profit from this regimen. This might reflect a heterogeneity of the patient group. The aim of this work is to define subgroups of patients with specific alterations of receptor expression and to profile the receptor expression individually. These receptor profiles might be used for the development of evidence-based "tailored" therapies. PATIENTS AND METHODS: Detrusor probes from bladder carcinoma patients (BCa, n=9 F, n=7 male) and interstitial cystitis patients (IC, n=9 female) were examined using confocal immunofluorescence and PCR. RESULTS: M2, M3, P2X1-3, and H1-3 mRNAs were demonstrated in detrusor tissue. As revealed by immunofluorescence, the M2 receptor expression was significantly higher in female compared to male BCa tissues. In addition, the M2 receptor was further upregulated in IC vs BCa in female detrusor. CONCLUSIONS: IC patients showed specific alterations of their receptor profile. Individual receptor profiles might be used to optimize medicinal therapies.

[High fat diet-induced molecular and physiological dysfunction of the urinary bladder]. / Hochfettdiät induziert molekulare und physiologische Dysfunktionen der Harnblase.

BACKGROUND: Obesity with its multiple comorbidities has become a global pandemia. We here report on the pathophysiological aspects of obesity-associated urinary bladder dysfunctions. MATERIAL AND METHODS: Our results are based on multiple in vitro and in vivo studies including a high fat diet (HFD) rat animal model of which the details are given in the cited publications. RESULTS: In cultured human detrusor muscle cells, obesity-related pathophysiological mechanisms were directly induced by the saturated free fatty acid palmitate. In HFD animals, we found serious fibrosis of the bladder wall and downregulation of the muscarinic M3-receptor leading to diminished contractility of the urinary bladder. Bariatric surgical intervention (sleeve gastrectomy) reversed the fibrosis. CONCLUSION: Our results support the relevance of obesity for urological bladder dysfunction. The epidemic dimension of obesity with its steadily growing number of cases requires a re-evaluation of this pathological condition in the urological context.