Presentation Authors: Xiaolong Wang*, Yiming Wang, Christian Gratzke, Bingsheng Li, Qingfeng Yu, Frank Strittmatter, Christian G. Stief, Munich, Germany, Chunxiao Liu, Guangzhou, China, People's Republic of, Martin Hennenberg, Munich, Germany
Introduction: Epidemiologic studies demonstrated a context between metabolic syndrome and lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). Recently, preliminary evidence suggested that this connection may be imparted by the metabolic hormone ghrelin, which promoted the proliferation of prostate stromal cells in cell culture, and smooth muscle contraction of human prostate tissues in vitro. In fact, contraction and growth in the prostate are the key processes causing urethral obstruction and LUTS attributed to BPH. Here, we provide evidence suggesting that ghrelin increases prostate size in vivo, and promotes growth and contraction at genomic level.
Methods: Ghrelin was applied (10Âµg/kg, i.p., 14d) to rats with testosteron-induced BPH. Prostate size was determined, and prostate tissues were subjected to microarray analysis. Expression of selected genes was analyzed for correlation with degree of BPH and ghrelin receptor (GHSR) expression in human prostate tissues and in cultured stromal cells (WPMY-1).
Results: Application of ghrelin increased prostate size in rats with testosteron-induced BPH. Expression of 893 genes was analyzed by microarray in these prostates. From all genes being upregulated 2-fold or more by ghrelin in BPH rats, a role for proliferation may be assumed at least for 6 genes, a role for regulation of smooth muscle contraction at least for 12, and a role for metabolism at least for 3. These findings were verified by analysis of mRNA of 12 of these genes together with mRNA for GHSR and prostate-specific antigen (PSA) by RT-PCR in human prostate tissues. For nearly all of them (11/12), mRNA levels correlated positivley with GHSR (R>0.5). A positive correlation with PSA was only suggested for two genes. Consistently, no correlation between GHSR and PSA was evident following analysis of mRNA levels or of band intensities after Western blot analysis of human prostate tissues. Regulation of these genes by ghrelin was confirmed in WPMY-1 cells. Stimulation with the GHRS agonist MK0677 induced upregulation (1.2-fold or more) of 8 of the genes, which were upreglated by ghrelin in rat prostates and which correlated with GHSR in human prostates.
Conclusions: Ghrelin increases prostate size in BPH, and upregulates genes with a potential to promote growth or smooth muscle contraction. Ghrelin may aggravate prostate smooth muscle tone and stromal growth independent of BPH. Ghrelin regulation of prostate growth and contraction may include genomic and nongenomic mechanisms.
Source of Funding: Deutsche Forschungsgemeinschaft (DFG), Chinese Scholarship Council (CSC)