Session: PD02: Benign Prostatic Hyperplasia: Basic Research & Pathophysiology
PD02-02: The role of transforming growth factor β in a prostatic fibrosis under suppression of dihydrotestosterone in high fat diet induced obesity rat model
Introduction: Although 5 alpha reductase inhibitors (5ARIs) can reduce prostatic volume by blocking production of dihydrotestosterone (DHT) and is widely used to treat symptomatic benign prostatic hyperplasia (BPH), the histological response to the treatment by 5ARIs is often heterogeneous and lower urinary tract symptoms can persist. Thus, a 5ARIs induced pathway related to treatment refractory is supposed to exist. To elucidate the pathways implicated to unsuccessful treatment for BPH patients, this study investigated changes in morphological and gene expression profiles in the prostate under DHT suppression using high fat diet induced obesity rat model. Methods: Male Wistar rats at 8 weeks old were divided into four groups; rats with normal diet group (ND, n=5), rats with high fat diet induced obesity group (HFD, n=5), HFD treated by dutasteride (D, n=4), and HFD treated by dutasteride and tranilast (D+T, n=4), which is known to inhibit TGFß. The high fat diet contains 32% fat. These rats were maintained for twelve weeks followed by two weeks treatment by oral administration of placebo or dutasteride (0.5mg/kg) or tranilast (150mg/kg) daily. Lateral lobes of prostate were harvested to evaluate prostatic weight, histological change and mRNA expression of IL1ß and TGFß in the prostate by qPCR. Results: HFD showed significantly increased body weight, visceral fat and prostatic weight as well as significant upregulation of gene expressions in IL1ß and TGFß compared to ND. In contrast, HFD treated by dutasteride demonstrated significantly decreased prostatic weight in association with downregulation of IL1ß and upregulation of TGFß with compared to HFD with placebo. Furthermore, dutasteride administration induced prostatic fibrosis as evidenced by masson trichrome staining whereas the addition of tranilast to dutasteride suppressed prostatic tissue fibrosis in association with reduced weight of prostatic tissue and downregulation of TGFß in group D+T compared to group D. Conclusions: This study demonstrated prostatic fibrosis in association with upregulation of TGFß as well as decreased prostatic weight and improvement of prostatic fibrosis by TGFß inhibition. These results suggest that TGFß signaling has an important role in development of prostatic fibrosis under 5ARIs treatment possibly leading to treatment refractory. Therefore, TGFß signaling pathway could be an therapeutic target for BPH. SOURCE OF Funding: JSPS KAKENHI Grant Number 20K18094
