Upregulation of androgen‐responsive genes and transforming growth factor‐β1 cascade genes in a rat model of non‐bacterial prostatic inflammation

Funahashi, Yasuhito; O’Malley, Katherine J.; Kawamorita, Naoki; Tyagi, Pradeep; DeFranco, Donald B.; Takahashi, Ryuji; Gotoh, Momokazu; Wang, Zhou; Yoshimura, Naoki

doi:10.1002/pros.22668

Cited by 34 publications

(41 citation statements)

References 33 publications

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“…In addition, the rat model of prostatic inflammation used in this study is not the direct model of BPH; however, we have shown that this rat model exhibits the upregulation of androgen receptor‐responsive genes and TGF‐β‐related genes in the prostate (Funahashi et al . ), which is similarly seen in human BPH tissues (O'Malley et al . ), and that increased IL‐18 expression induced by inflammasome activation is similarly found in the formalin‐induced rat prostatic inflammation model (Kashyap et al .…”

Section: Discussionsupporting

confidence: 58%

Bladder overactivity and afferent hyperexcitability induced by prostate‐to‐bladder cross‐sensitization in rats with prostatic inflammation

Funahashi

Takahashi

Mizoguchi

et al. 2019

The Journal of Physiology

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Key points There is clinical evidence showing that prostatic inflammation contributes to overactive bladder symptoms in male patients; however, little is known about the underlying mechanisms In this study, we investigated the mechanism that prostatic inflammation causes detrusor overactivity by using a rat model of chemically induced prostatic inflammation. We observed a significant number of dorsal root ganglion neurons with dichotomized afferents innervating both prostate and bladder. We also found that prostatic inflammation induces bladder overactivity and urothelial NGF overexpression in the bladder, both dependent on activation of the pelvic nerve, as well as changes in ion channel expression and hyperexcitability of bladder afferent neurons. These results indicate that the prostate‐to‐bladder cross‐sensitization through primary afferent pathways in the pelvic nerve, which contain dichotomized afferents, could be an important mechanism contributing to bladder overactivity and afferent hyperexcitability induced by prostatic inflammation. Abstract Prostatic inflammation is reportedly an important factor inducing lower urinary tract symptoms (LUTS) including urinary frequency, urgency and incontinence in patients with benign prostatic hyperplasia (BPH). However, the underlying mechanisms inducing bladder dysfunction after prostatic inflammation are not well clarified. We therefore investigated the effects of prostatic inflammation on bladder activity and afferent function using a rat model of non‐bacterial prostatic inflammation. We demonstrated that bladder overactivity, evident as decreased voided volume and shorter intercontraction intervals in cystometry, was observed in rats with prostatic inflammation versus controls. Tissue inflammation, evident as increased myeloperoxidase activity, and IL‐1α, IL‐1β, and IL‐6 levels inside the prostate, but not in the bladder, following intraprostatic formalin injection induced an increase in NGF expression in the bladder urothelium, which depended on activation of the pelvic nerve. A significant proportion (18–19%) of dorsal root ganglion neurons were double labelled by dye tracers injected into either bladder or prostate. In rats with prostatic inflammation, TRPV1, TRPA1 and P2X2 increased, and Kv1.4, a potassium channel α‐subunit that can form A‐type potassium (KA) channels, decreased at mRNA levels in bladder afferent and double‐labelled neurons vs. non‐labelled neurons, and slow KA current density decreased in association with hyperexcitability of these neurons. Collectively, non‐bacterial inflammation localized in the prostate induces bladder overactivity and enhances bladder afferent function. Thus, prostate‐to‐bladder afferent cross‐sensitization through primary afferents in the pelvic nerve, which contain dichotomized afferents, could underlie storage LUTS in symptomatic BPH with prostatic inflammation.

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Section: Discussionsupporting

confidence: 58%

Bladder overactivity and afferent hyperexcitability induced by prostate‐to‐bladder cross‐sensitization in rats with prostatic inflammation

Funahashi

Takahashi

Mizoguchi

et al. 2019

The Journal of Physiology

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“…2, 6, 7 Cytokines secreted from inflammatory cells stimulate androgen receptor activity in prostate cancer cells. 22, 23 We have previously reported molecular changes similar to those identified in human BPH specimens in an abacterial rat model of prostatitis, 18 which is characterized by infiltration of inflammatory cells up to 4 weeks after intraprostatic formalin injection. In this study, we further demonstrated that E. coli-induced chronic inflammation also induces the long-lasting (12 weeks) upregulation of epithelial androgen-responsive and stromal TGF-β1 cascade genes.…”

Section: Discussionmentioning

confidence: 78%

“…18 In this study, we evaluated whether chronic prostatic inflammation for 12 weeks induces the elevated expression of androgen and TGF-β1 cascade genes and assessed the effects of a COX-2 inhibitor on the expression of these genes using a rat model of bacterial prostatitis.…”

Section: Introductionmentioning

confidence: 99%

Influence ofE. coli-induced prostatic inflammation on expression of androgen-responsive genes and transforming growth factor beta 1 cascade genes in rats

et al. 2014

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Background Prostatic inflammation is reportedly associated with the development of prostatic hyperplasia. We investigated the effects of prostatic inflammation on expression levels of androgen-responsive genes and growth factors in the rat prostate. Methods Prostatic inflammation was induced by Escherichia coli (strain 1677) injection (0.2 mL of 1 × 108 CFU/mL) into the prostatic urethra of male Sprague-Dawley rats, and ventral lobes of the prostate were harvested on day 84. Rats were given 10 mg/kg celecoxib during the last month in the COX-2 inhibitor treated group. Histopathology and multiplex ELISA for inflammation-related proteins were performed. Glandular epithelial cells and stromal regions were separately isolated using laser-capture microdissection (LCM). Real-time RT-PCR was performed to examine mRNA levels of androgen-responsive genes in the epithelium and TGF-β1 cascade genes in the stroma. Results Hematoxylin and eosin staining showed that mild inflammation was distributed diffusely throughout the prostate. Polymorphonuclear cells infiltrated the slightly edematous stroma, but no morphological changes were observed in the epithelium. Immunohistochemically, expression of androgen receptor and TGF-β1 in addition to IL-6 and COX-2 were enhanced in the E. coli inoculated rats. All of these factors were suppressed in the celecoxib-treated rats. Upregulation of IL-1α, IL-1β, IL-6, and RANTES in the E. coli-inoculated rats was normalized by celecoxib treatment. Significant upregulation of androgen receptor and androgen-responsive genes such as Eaf2, ELL2, FKBP5, calreticulin and ornithine decarboxylase was observed in the LCM-dissected epithelium. Also TGF-β1 and its downstream cascade genes such as Hic-5, collagen 1, and fibronectin were upregulated significantly in the LCM-dissected stroma. The COX-2 inhibitor treatment suppressed upregulation of these genes. Conclusions Prostatic inflammation changed the expression of androgen-responsive genes in the epithelium and TGF-β1 cascade genes in the stroma. Activation of TGF-β1 cascade genes in the inflamed stroma, as well as altered androgen-responsive gene expression in the epithelium, might be involved in the development of BPH.

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“…Group V: BPH+CLX as a positive control (received 10 mg/kg celecoxib in combination with TP s.c by gavage) (20). …”

Section: Methodsmentioning

confidence: 99%

Withania coagulans Extract Induces Cell Apoptosis and Inhibits COX-2 Expression in a Rat Model of Benign Prostatic Hyperplasia

2016

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BackgroundPhytotherapy is a popular treatment option in cases of benign prostatic hyperplasia (BPH), with many different herbal products being used for the treatment of this condition. Withania coagulans (WC) is an herbal medicine that has shown anti-tumoral, anti-inflammatory, and antioxidant effects.ObjectivesThis study examined the effect of Withania coagulans extract (WCE) on prostatic cell apoptosis and cyclooxygenase-2 (COX-2) expression in cases of benign prostatic hyperplasia (BPH) in rats.MethodsForty Wistar rats were equally divided into five groups: control, sham, BPH, BPH + WCE, and BPH + CLX (celecoxib) as a positive control group. The induction of BPH was achieved via the subcutaneous injection of 3 mg/kg of testosterone propionate (TP) daily for 28 days. The animals received WCE, celecoxib, or distilled water by oral gavage accompanied by the TP injection. After four weeks, the prostate glands of the rats were weighed to measure the prostatic index (PI). The ventral lobes of the prostates were dissected and processed with paraffin blocks in order to study the number of mast cells. A TUNEL analysis was performed to evaluate the cell apoptosis, while the expression of COX-2 was examined using immunohistochemistry.ResultsBPH was obvious in the ventral lobe of the prostate, and the administration of WCE markedly decreased the PI and the number of mast cells (P < 0.001) in the BPH rats. Additionally, the WCE treatment induced prostatic cell apoptosis when compared to the BPH group. Furthermore, following the WCE treatment, the expression of COX-2 in the prostatic tissues was significantly decreased when compared to the BPH groups.ConclusionsAccording to the results of this study, WCE was effective in the treatment of BPH in rats. It may therefore have beneficial effects in the treatment of patients with BPH.

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Upregulation of androgen‐responsive genes and transforming growth factor‐β1 cascade genes in a rat model of non‐bacterial prostatic inflammation

Cited by 34 publications

References 33 publications

Bladder overactivity and afferent hyperexcitability induced by prostate‐to‐bladder cross‐sensitization in rats with prostatic inflammation

Bladder overactivity and afferent hyperexcitability induced by prostate‐to‐bladder cross‐sensitization in rats with prostatic inflammation

Influence ofE. coli-induced prostatic inflammation on expression of androgen-responsive genes and transforming growth factor beta 1 cascade genes in rats

Withania coagulans Extract Induces Cell Apoptosis and Inhibits COX-2 Expression in a Rat Model of Benign Prostatic Hyperplasia

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