Ghrelin Aggravates Prostate Enlargement in Rats with Testosterone-Induced Benign Prostatic Hyperplasia, Stromal Cell Proliferation, and Smooth Muscle Contraction in Human Prostate Tissues
Ghrelin Aggravates Prostate Enlargement in Rats with Testosterone-Induced Benign Prostatic Hyperplasia, Stromal Cell Proliferation, and Smooth Muscle Contraction in Human Prostate Tissues
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DOI：
10.1155/2019/4748312
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发表时间：
2019-11
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通讯作者：
Xiaolong Wang;Yiming Wang;C. Gratzke;C. Sterr;Qingfeng Yu;Bingsheng Li;F. Strittmatter;A. Herlemann;A. Tamalunas;B. Rutz;A. Ciotkowska;R. Waidelich;Chunxiao Liu;C. Stief;M. Hennenberg
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作者：
Xiaolong Wang;Yiming Wang;C. Gratzke;C. Sterr;Qingfeng Yu;Bingsheng Li;F. Strittmatter;A. Herlemann;A. Tamalunas;B. Rutz;A. Ciotkowska;R. Waidelich;Chunxiao Liu;C. Stief;M. Hennenberg
流行病学研究揭示了下尿路症状（LUTS）提示良性前列腺增生（BPH）和代谢综合征之间的背景。然而，这种关系的分子机制在很大程度上是未知的。前列腺增大和前列腺平滑肌张力增加是提示BPH的LUTS病理生理学的重要因素。在本研究中，我们研究了代谢激素ghrelin对实验诱导的BPH大鼠前列腺肥大，培养的人前列腺基质细胞（WPMY-1）的生长和人前列腺组织平滑肌收缩的影响。胃饥饿素（每日20 nmol/kg，p.o.，2周）增加前列腺的大小与睾酮诱导的BPH大鼠。微阵列确定了114 ghrelin上调基因（2倍或更多），在这些前列腺中，与生长，平滑肌收缩，或代谢的可能作用。选择12个基因进行进一步分析。在人前列腺组织中，其中11个基因的mRNA水平与生长激素释放肽受体（GHSR）表达呈正相关，但只有两个与BPH的程度。因此，在人前列腺组织中GHSR表达水平与BPH之间没有明显的相关性。在WPMY-1细胞中，GHRS激动剂MK 0677上调了11个选定的基因。EdU测定、集落形成、增殖标志物、流式细胞术和活力显示MK 0677诱导WPMY-1细胞增殖。在肌电测量中，GHSR激动剂增强了人前列腺条的收缩。总之，生长激素释放肽可能加重前列腺肥大，基质细胞生长，前列腺平滑肌收缩。Ghrelin可能独立于BPH恶化尿道梗阻，使Ghrelin系统成为BPH LUTS治疗的一个有吸引力的新靶点。
Epidemiologic studies revealed a context between lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and metabolic syndrome. However, molecular mechanisms underlying this relationship are largely unknown. Prostate enlargement and increased prostate smooth muscle tone are important factors in the pathophysiology of LUTS suggestive of BPH. In the present study, we studied effects of the metabolic hormone ghrelin on prostate enlargement in rats with experimentally induced BPH, growth of cultured stromal cells from human prostate (WPMY-1), and smooth muscle contraction of human prostate tissues. Ghrelin (20 nmol/kg daily, p.o., 2 weeks) increased prostate size in rats with testosterone-induced BPH. Microarray identified 114 ghrelin-upregulated genes (2-fold or more) in these prostates, with possible roles in growth, smooth muscle contraction, or metabolism. 12 genes were selected for further analyses. In human prostate tissues, mRNA levels of 11 of them correlated positively with ghrelin receptor (GHSR) expression, but only two with the degree of BPH. Accordingly, no correlation was evident between GHSR expression level and BPH in human prostate tissues. In WPMY-1 cells, the GHRS agonist MK0677 upregulated 11 of the selected genes. MK0677 induced proliferation of WPMY-1 cells, shown by EdU assay, colony formation, proliferation markers, flow cytometry, and viability. In myographic measurements, GHSR agonists enhanced contractions of human prostate strips. Together, ghrelin may aggravate prostate enlargement, stromal cell growth, and prostate smooth muscle contraction in BPH. Ghrelin may deteriorate urethral obstruction independently from BPH, qualifying the ghrelin system as an attractive new target to be tested for LUTS treatment in BPH.