Bladder outlet obstruction is a common urological condition. We aimed to summarize available evidences about bladder outlet obstruction-induced molecular and morphological alterations occurring in human bladder. We performed a literature search up to December 2017 including clinical and preclinical basic research studies on humans. The following search terms were combined: angiogenesis, apoptosis, bladder outlet obstruction, collagen, electron microscopy, extracellular matrix, fibrosis, hypoxia, histology, inflammation, innervation, ischemia, pressure, proliferation, remodeling, suburothelium, smooth muscle cells, stretch, urothelium. We identified 36 relevant studies. A three-stages model of bladder wall remodeling can be hypothesized involving an initial hypertrophy phase, a subsequent compensation phase and a later decompensation. Histological and molecular alterations occur in the following compartments: urothelium, suburothelium, detrusor smooth muscle cells, detrusor extracellular matrix, nerves. Cyclic stretch, increased hydrostatic and cyclic hydrodynamic pressure and hypoxia are stimuli capable of modulating multiple signaling pathways involved in this remodeling process. Bladder outlet obstruction leads to progressive bladder tissue remodeling in humans. Multiple signaling pathways are involved.

/pdf/progressive-bladder-remodeling-due-to-bladder-outlet-ef9z7e50jj.pdf

Progressive bladder remodeling due to bladder outlet obstruction: a systematic review of morphological and molecular evidences in humans

Background and Purpose
Medical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) targets smooth muscle contraction in the prostate, or prostate growth. However, current therapeutic options are insufficient. Here, we investigated the role of Rac in the control of smooth muscle tone in human prostates and growth of prostate stromal cells.

Experimental Approach
Experiments were performed using human prostate tissues from radical prostatectomy and cultured stromal cells (WPMY-1). Expression of Rac was examined by Western blot and fluorescence staining. Effects of Rac inhibitors (NSC23766 and EHT1864) on contractility were assessed in the organ bath. The effects of Rac inhibitors were assessed by pull-down, cytotoxicity using a cell counting kit, cytoskeletal organization by phalloidin staining and cell growth using an 5-ethynyl-2′-deoxyuridine assay.

Key Results
Expression of Rac1–3 was observed in prostate samples from each patient. Immunoreactivity for Rac1–3 was observed in the stroma, where it colocalized with the smooth muscle marker, calponin. NSC23766 and EHT1864 significantly reduced contractions of prostate strips induced by noradrenaline, phenylephrine or electrical field stimulation. NSC23766 and EHT1864 inhibited Rac activity in WPMY-1 cells. Survival of WPMY-1 cells ranged between 64 and 81% after incubation with NSC23766 (50 or 100 μM) or EHT1864 (25 μM) for 24 h. NSC23766 and EHT1864 induced cytoskeletal disorganization in WPMY-1 cells. Both inhibitors impaired the growth of WPMY-1 cells.

Conclusions and Implications
Rac may be a link connecting the control of prostate smooth muscle tone with proliferation of smooth muscle cells. Improvements in LUTS suggestive of BPH by Rac inhibitors appears possible.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13099

Inhibition of prostate smooth muscle contraction and prostate stromal cell growth by the inhibitors of Rac, NSC23766 and EHT1864.

Human bladder smooth muscle cells (HBSMCs) were subjected to pressure cycles of up to 200 cm H2O to a pressure of 0 cm H2O for 24 hours. The total RNA extracted from each group was subjected to microarray analysis. miR-3180-5p emerged as the most overexpressed of all the differentially expressed microRNAs, and this finding was validated by PCR. We then used CCK-8 to quantify cell proliferation after liposome-mediated transfection. Subsequently, we investigated the change in PODN and its downstream signaling proteins, including cyclin-dependent kinase 2 (cdk2) and p21. In addition, flow cytometry was performed to quantify cell-cycle distribution. The results show that miR-3180-5p, the microRNA that was most overexpressed in response to HP, reduced the expression of PODN and podocan (p = 0.004 and p = 0.041, respectively). Silencing of PODN via miR-3180-5p overexpression revealed a significant promotion of cell proliferation increased in the CCK-8 experiment, p = 0.00077). This cell proliferation was accompanied by an increase in cdk2 expression (p = 0.00193) and a decrease in p21 expression (p = 0.0095). The percentage of cells in (S + G2/M) improved after transfection (p = 0.002). It was apparent that HP upregulates miR-3180-5p, which inhibits the expression of PODN and promotes HBSMC proliferation via the cdk2 signaling pathway.

/pdf/mir-3180-5p-promotes-proliferation-in-human-bladder-smooth-42hoi3do8y.pdf

MiR 3180-5p promotes proliferation in human bladder smooth muscle cell by targeting PODN under hydrodynamic pressure.

It is well known that specific mechanical stimuli induce positive changes in the physiological function and status of a number of cell types. However, an in‑depth understanding of the application of mechanical forces has yet to be developed. The aim of the present study was to explore the optimal elongation and frequency of stretch‑induced proliferation of human bladder smooth muscle cells (HBSMCs) and to investigate the mechanism involved in this process. HBSMCs were seeded in a silicone membrane and subjected to cyclic stretch of 2.5, 5, 10 and 15% equibiaxial elongation at frequencies of 0.05, 0.1, 0.2, 0.5 and 1 Hz, respectively. Bromodeoxyuridine (BrdU) assays were used to detect the proliferative activity of each group. To further determine the mechanism of the cell proliferation process triggered by physiological cyclic stretch, the expression of PI3K/SGK1/Akt/Kv1.3 was investigated at the transcriptional and translational levels by RT‑PCR and western blot analysis, respectively. Optimal physiological stretch was established as 5% elongation at a frequency of 0.1 Hz, whereby HBSMCs revealed a marked increase in proliferative activity compared with the other groups, including the non‑stretched group, which served as the control (P<0.05). The expression of PI3K/SGK1/Kv1.3; however, not Akt, were upregulated by cyclic stretch as compared with the control group. When separately treated with inhibitors of SGK1 and Kv1.3, increased stretch‑induced proliferation was largely eliminated. These results markedly indicate that cyclic stretch induces the proliferation of HBSMCs and the PI3K‑SGK1‑Kv1.3 pathway is involved in this process, either fully or at least partially, rather than its related pathway, PI3K‑Akt.

/pdf/increased-proliferation-of-human-bladder-smooth-muscle-cells-3hmimh782t.pdf

Increased proliferation of human bladder smooth muscle cells is mediated by physiological cyclic stretch via the PI3K‑SGK1‑Kv1.3 pathway

Rac1 silencing, NSC23766 and EHT1864 reduce growth and actin organization of bladder smooth muscle cells

Objectives: To examine the role of Ras-related C3 botulinum toxin substrate 1, mitogen-activated protein kinase kinase 1/2 and extracellular regulated protein kinases 1/2 in the cyclic hydrodynamic pressure-induced proliferation of human bladder smooth muscle cells.



Methods:  Human bladder smooth muscle cells were exposed to cyclic hydrodynamic pressures in vitro with defined parameters (static, 100 cmH2O, 200 cmH2O and 300 cmH2O pressure) for 24 h. The proliferation of cells was assessed by flow cytometry. Ras-related C3 botulinum toxin substrate 1, mitogen-activated protein kinase kinase 1/2 and extracellular regulated protein kinases 1/2 messenger ribonucleic acid, and protein expression was analyzed by real-time polymerase chain reaction and Western blot. Specificity of the Rac1 was determined with real-time polymerase chain reaction and Western blot technique with small interfering ribonucleic acid transfection and Rac1 inhibitor (NSC23766).



Results:  The proliferation of human bladder smooth muscle cells was increased. Ras-related C3 botulinum toxin substrate 1, mitogen-activated protein kinase kinase 1/2 and extracellular regulated protein kinases 1/2 were activated by 200 and 300 cmH2O cyclic hydrodynamic pressure compared with static and 100 cmH2O pressure. The “knockdown” of activation of Rac1 using target small interfering ribonucleic acid transfection and Rac1 inhibitor (NSC23766) decreased proliferation of human bladder smooth muscle cells, and downregulated mitogen-activated protein kinase kinase 1/2, extracellular regulated protein kinases 1/2.



Conclusion:  The Rac1 pathway is activated in mechanotransduction and regulation of human bladder smooth muscle cell proliferation in response to cyclic hydrodynamic pressure.

Effect of cyclic hydrodynamic pressure-induced proliferation of human bladder smooth muscle through Ras-related C3 botulinum toxin substrate 1, mitogen-activated protein kinase kinase 1/2 and extracellular regulated protein kinases 1/2

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Effect of cyclic hydrodynamic pressure-induced proliferation of human bladder smooth muscle through Ras-related C3 botulinum toxin substrate 1, mitogen-activated protein kinase kinase 1/2 and extracellular regulated protein kinases 1/2