Wang Xiaolong, Guo Linfa, Liu Guiyong, Liu Tongzu
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.
Qianjiang Central Hospital of Hubei Province, Qianjiang, People's Republic of China.
Diabetes Metab Syndr Obes. 2023 Oct 19;16:3261-3273. doi: 10.2147/DMSO.S420258. eCollection 2023.
Leptin is a metabolic peptide hormone produced by adipocytes, with proven roles in proliferation of prostate cancer cells and of prostate cells in animal models of benign prostatic hyperplasia (BPH). Thus, the role of leptin as a molecular link connecting BPH and lower urinary tract symptoms (LUTS) suggestive of BPH with metabolic symptoms appears feasible but is still unknown. In fact, a connection between metabolic syndrome and BPH is becoming increasingly evident from epidemiologic studies. Key factors of Lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH/LUTS) are increased prostate smooth muscle tone, and prostate enlargement. Here, we examined the effects of leptin on contraction of human prostate smooth muscle and on growth of stromal cells.
We performed microarray analysis to identify genes (fold change ≥ 1.5) associated with BPH/LUTS progression, such as those involved in proliferation, apoptosis, and mitochondrial metabolism, in rat prostate tissue (data from GSE129561). We then used electric field stimulation (EFS) to induce frequency-dependent, neurogenic contractions of human prostate strips, which were enhanced by leptin. We also examined the effect of leptin on human prostate stromal cells (WPMY-1) and found increased cell proliferation and viability upon exposure. To explore the underlying mechanism, we conducted mitochondrial stress assay using near-infrared (NIR) fluorescent dye and flow cytometry (FACS) analysis and observed reduced cellular apoptosis and preserved mitochondrial membrane potential (∆ψM) after leptin treatment.
Microarray analysis reveals that leptin regulates prostate smooth muscle contraction and stromal cell proliferation, shedding new light on its involvement in BPH/LUTS pathogenesis and mitochondrial function. We found that leptin enhanced the proliferation rate of prostate stromal cells relative to the control group (0.67 ± 0.05 vs 0.54 ± 0.08, p-value= 0.024). Moreover, leptin (100 ng/mL) potentiated the frequency-dependent, neurogenic contractions of prostate strips elicited by EFS (p= 0.047 between leptin and control group). We also show that leptin treatment increased the mitochondrial membrane potential of prostate stromal cells and inhibited mitochondrial apoptosis.
Our results indicate that leptin stimulates the contractility and proliferation of smooth muscle and stromal cells in the human prostate, implying a potential role for leptin in exacerbating BPH/LUTS in obese men. Leptin modulation may be a beneficial therapeutic strategy for patients with metabolic syndrome and BPH/LUTS. Further studies are warranted to elucidate the mechanisms and implications of the leptin system in BPH/LUTS.
瘦素是一种由脂肪细胞产生的代谢肽激素，在前列腺癌细胞增殖以及良性前列腺增生（BPH）动物模型中的前列腺细胞增殖方面已被证实具有作用。因此，瘦素作为连接BPH与提示BPH合并代谢症状的下尿路症状（LUTS）的分子纽带，其作用似乎是可行的，但仍不清楚。事实上，从流行病学研究来看，代谢综合征与BPH之间的联系越来越明显。与良性前列腺增生相关的下尿路症状（BPH/LUTS）的关键因素是前列腺平滑肌张力增加和前列腺增大。在此，我们研究了瘦素对人前列腺平滑肌收缩和基质细胞生长的影响。
我们进行了微阵列分析，以鉴定大鼠前列腺组织中与BPH/LUTS进展相关的基因（倍数变化≥1.5），例如参与增殖、凋亡和线粒体代谢的基因（数据来自GSE129561）。然后，我们使用电场刺激（EFS）诱导人前列腺条带的频率依赖性神经源性收缩，瘦素可增强这种收缩。我们还研究了瘦素对人前列腺基质细胞（WPMY-1）的影响，发现暴露后细胞增殖和活力增加。为了探究潜在机制，我们使用近红外（NIR）荧光染料进行线粒体应激试验并通过流式细胞术（FACS）分析，观察到瘦素处理后细胞凋亡减少且线粒体膜电位（∆ψM）得以保留。
微阵列分析表明，瘦素调节前列腺平滑肌收缩和基质细胞增殖，为其在BPH/LUTS发病机制和线粒体功能中的作用提供了新的线索。我们发现，相对于对照组，瘦素提高了前列腺基质细胞的增殖率（0.67±0.05对0.54±0.08，p值 = 0.024）。此外，瘦素（100 ng/mL）增强了EFS引发的前列腺条带的频率依赖性神经源性收缩（瘦素组与对照组之间p = 0.047）。我们还表明，瘦素处理增加了前列腺基质细胞的线粒体膜电位并抑制了线粒体凋亡。
我们的结果表明，瘦素刺激人前列腺平滑肌和基质细胞的收缩性和增殖，这意味着瘦素在加重肥胖男性的BPH/LUTS方面可能具有潜在作用。瘦素调节可能是代谢综合征和BPH/LUTS患者的一种有益治疗策略。有必要进一步研究以阐明瘦素系统在BPH/LUTS中的机制和意义。
