雄激素在肾结石形成过程中作用的研究
摘要
背景
尿石症是泌尿外科的最常见的疾病之一,而男性结石的发病率远远高于女性,以前对结石发病机制的研究多集中在动物模型中雄激素对尿液成分的影响与结石形成的关系,即尿液中草酸等促进结石成分的过饱和以及骨桥蛋白,枸橼酸等抑制结石形成的成分的减少,而近年发现仅有尿液中结石成分过饱和、抑制结石成分的下降是很难形成肾结石的,肾小管上皮细胞在肾结石产生的过程中发挥了十分重要的作用,事实上,只有结晶粘附于肾小管上皮细胞上才能继续生长,变成有临床症状的结石。但是雄激素在肾结石患者肾小管上皮细胞的作用方面,目前极少有研究涉及,而这方面的研究,能更好的阐释肾结石发病的性别差异的问题,能为肾结石的发病机制的研究提供新的研究思路和方向。
研究目的
1、探讨雄激素是否为肾结石的诱发因素之一,即雄激素是否促进了肾结石的产程。
2、探讨雄激素促进肾结石产生的机制,即雄激素对肾小管上皮细胞的作用及其作用机制。
研究内容
1、选取接受经皮肾镜检查碎石手术(PCNL术)的成年男性患者,和体检合格的正常男性患者,留取患者血浆标本采用酶联免疫法(ELISA)检测患者睾酮和游离睾酮水平；并于手术结束时超声引导下穿刺获得肾小管上皮组织；术后留取患者结石成分,采用傅立叶转换红外光谱测定结石成分。然后采用正常肾组织作为对照,采用免疫组化方法检测结石患者肾小管上皮组织的雄激素受体表达情况以及丛生蛋白的表达情况,比较二者表达与各自对照组有无差别。
2、培养HK-2细胞,然后在培养基中加入不同终浓度的睾酮(1nM、10nM、100nM、1000 nM)以及雄激素拮抗剂氟他胺(100 nM),分别作用6小时,24小时和72小时,然后采用MTT法检测睾酮对HK-2细胞的生长抑制情况,再采用流式细胞技术检测细胞的凋亡情况。
3、检测上述条件下睾酮及雄激素受体拮抗剂处理过的HK-2细胞的凋亡相关蛋白丛生蛋白的表达情况并比较其两种亚型分泌型(s-clusterin)和细胞核型(n-clusterin)表达的差别,采用RT-PCR方法和Western-blotting方法检测上述二者在mRNA水平和蛋白水平表达的差异,了解他们在睾酮诱导的肾小管上皮细胞凋亡过程中所发挥的作用。
结果
1、所有男性结石患者术后结石红外光谱测定结石成分,均以草酸钙成分为主,包括一水草酸钙和二水草酸钙。所有入选对象ELISA法检测血睾酮和游离睾酮结果表明,肾结石患者的血睾酮和游离睾酮水平均高于正常对照人群(P<0.01),而且血睾酮和游离睾酮二者具有明显的正相关关系(P<0.05)。免疫组化研究结果表明,肾小管上皮细胞的细胞核雄激素受体表达阳性,近曲小管、远曲小管、集合管均有表达,以近曲小管、远曲小管为主,而且结石患者肾组织表达强度明显高于正常对照组(P<0.05)；同样,免疫组化结果表明,在肾小管上皮细胞的细胞浆中丛生蛋白表达阳性,结石患者的表达水平高于正常对照组(P<0.05)。
2、体外HK-2细胞学实验表明,睾酮能抑制细胞增殖,MTT法检测细胞生长抑制曲线,表明随着睾酮浓度的增高,作用时间的延长,睾酮对细胞生长的抑制明显升高(P<0.01),最大的抑制率为1000nM,作用72小时；其次睾酮能诱导细胞发生凋亡,流式细胞仪检测表明,经过睾酮处理的HK-2细胞的凋亡百分率明显高于对照组细胞,而且同样随着睾酮浓度的升高、处理时间的延长,凋亡率明显升高,并且具有明显统计学意义(P<0.05)。
3、检测经睾酮处理过的HK-2细胞丛生蛋白表达情况,发现睾酮处理过以后,采用RT-PCR方法检测mRNA表达、采用western-blotting法检测蛋白水平的表达,结果发现s-clusterin蛋白表达下降,而n-clusterin蛋白表达升高,二者共同作用参与了HK-2细胞的凋亡过程。
结论
1、男性肾结石患者的血总睾酮水平、游离睾酮水平均明显高于正常对照组,肾结石肾组织的雄激素受体表达明显高于正常对照,所以推测雄激素在肾脏草酸钙结石产生过程中发挥了重要的作用,在全身循环代谢和肾脏肾小管上皮细胞都产生影响,促进了肾结石的产生。
2、睾酮能够抑制肾小管上皮细胞增殖,诱导肾小管上皮细胞发生凋亡,并且具有剂量和时间依赖效应,因此这种对肾小管上皮细胞的作用很可能是其参与肾结石形成的途径之一
3、经睾酮处理后肾小管上皮细胞,RT-PCR结果表明clusterin的mRNA水平升高,western-blotting方法检测结果表明N-clusterin的蛋白水平升高,而S-clusterin下降,我们认为二者均在肾小管上皮细胞凋亡过程中发挥重要的作用。
4、本研究对雄性激素在肾结石形成过程中的作用及其机制做了详细的研究,探讨了雄激素和雄激素受体在肾结石患者中的水平,并且进一步分析了睾酮对肾小管上皮细胞的作用以及机制,以及丛生蛋白在此过程中的作用,从而在肾小管上皮细胞损伤的方面阐释了雄激素在肾结石形成过程中的作用以及结石好发于男性的机制。
Backgrounds
The prevalence of renal stone in men was much higher than in the women, but the reason why the gender disparity exist is always unclear. Some studies had found that the urinary citrate level of females is much higher than the males. In the recent years, the study on the kidey stone is still focus on the urinary Supersaturation like calcium, oxalate, and the insufficient urinary inhibitors for formation of stone like Citrate, Osteopontin, Magnesium. Actually, in addition to urine constituents, the renal tubule epithelial cells play a role in the formation of stone. Previous studies have found that lethal renal epithelial cellular injury promotes crystal nucleation, aggregation and retention. Another study revealed that the adherence of crystals to pericellular matrixes may encompass more than their simple fixation to the polysaccharide Hyaluronan (HA). Calcium oxalate crystal retention is not prevented by coating crystals with urinary constituents such as glycoproteins and, therefore, may depend primarily on the surface properties of the renal tubular epithelium. However, the relation of the androgen and kidney stone is not still clear, and the effect of androgen on the renal tubular epithelial cell is unknown, either. Thus we speculate that perhaps androgen cytotoxic to the renal tubule epithelial cell, which induce the formation of kidney stone.
Objective
1. The purpose of this study was to determine whether testosterone would contribute to the nephrolithiasis.
2. To evaluate the effects of testosterone at different levels on human renal tubular epithelial cells (HK-2) and whether the testosterone has the effect of pro-apoptosis on the renal tubular epithelial cells
3. To evaluate the expression of clusterin in the renal tubular epithelial cell of the patients with renal stone, and identify the differently expressed proteins of two isoforms of clusterin in HK-2 cells treated with testosterone at different levels, so as to find the exact effect of the clusterin in the HK-2 cells treated with testosterone and provide new ways for further kidney stone formation.
Methods
1. Patients with renal calculi undergoing percutaneous nephrolithotomy (PCNL) were included, whose stones were analysed with a transform-infrared (FT-IR) spectrometer, but all the patients participated in this study were excluded the urinary tract infection and hydronephrosis, at the end of procedure ultrasound-guided puncture biopsy was performed to acquire the kidney tissue, while kidney tissues from autopsy archived in pathology department were obtained as the control. The expression of androgen receptor and clusterin in renal tubular epithelial cell were evaluated by immunohistochemistry. Besides this, the blood of all the subjects was collected into a tube containing 2% heparin in the morning, and the total and free serum testosterone levels were measured for each person by enzyme linked immunosorbent assay(ELISA).
2. Normal HK-2 cells were cultured in vitro and the culture medium was changed with serum-free medium after cell growth to confluence. Testosterone with different concentrations or testosterone combined flutamide were then added and the cells were incubated for 6h,24h,48h or 72h, respectively, then the ratio of cell viability was measured by MTT, while cell apoptosis was measured by annexin V/propidium iodide (PI) staining.
3. The expression two activation isoforms of clusterin were analyzed by western blotting, and the mRNA level of clusterin was measured by RT-PCR, after the HK-2 cells incubated with different levels testosterone or incubated with both testosterone and flutamide. Then the results were analyzed to clarity the function of clusterin in the apoptosis of HK-2 cell induced by testosterone.
Results
1. All the calculi included calcium oxalate monohydrate and calcium oxalate dihydrate, and a small quantity of calculi also contained the protein or uric acid. The mean serum levels of total testosterone and free testosterone in patients with kidney stone were 13.29±4.79ng/ml,28.58±4.70 pg/ml; and the levels of total testosterone, free testosterone in control group was7.30±0.82 ng/ml,24.91±4.47 pg/ml. There was significant difference of the hormones level between patients and healthy men, respectively (P<0.01). Moreover, there was a significant correlation between the total testosterone levels and free testosterone levels (r=0.824, p<0.0001). The AR expression in renal tissues was localized to cell nuclei of the renal distal tubule epithelial cell. Immunohistochemistry assessment showed up-regulation of AR in patients with kidney stones (P<0.05). Immunohistochemistry assessment showed the expression of clusterin was located in the cytoplasm of renal tubular epithelial cell, and the expression in the cells of patients was higher than in the controls significantly(P<0.05).
2. The results showed that the ratio of cell viability inhibition of HK-2 cells increased as the testosterone concentration increased and as the time increased. Maximal inhibition of proliferation was achieved after 72 h of cell exposure to testosterone 1000nM,72h, and this inhibition was time- and dose-dependent. Cells undergoing early apoptosis were usually characterized by the degree of phosphatidylserine exposure with the testosterone. HK-2 cells treated with testosterone exhibited a significant increase, which indicated that testosterone induced apoptosis in HK-2 cells in a dose- and time-dependent manner but did not cause obvious necrosis.
3. HK-2 cells treated with testosterone were analyzed by western blotting that detected the expression of clusterin. The result showed that testosterone activated the expression of N-clusterin. We also found that the down-regulation of S-clusterin in the cells exposed to testosterone, and the expression of S-clu was also shown, which was much weaker than the N-clu. The mRNA expression levels of clusterin in the HK-2 after exposure to testosterone was measured by quantitative RT-PCR.
Conclusions
1. We found both serum total testosterone and free testosterone in the male patients with renal calculi were higher in comparison with healthy men, and the expression of androgen receptor in kidney of patients was also stronger than the controls. This study indicates that total and free testosterone may play an important role in the formation of kidney calclui in male patients.
2. The HK-2 cells incubated with testosterone showed a significant dose- and time-dependent decrease in viability, and the testosterone also could induced the HK-2 to apoptosis. Therefore, the effect of pro-apoptosis on the renal tubular epithelial cell could play an important role in formation of kidney stone.
3. Our findings showed that HK-2 cell exposure to testosterone resulted in a marked accumulation of N-clusterin, which is considered an apoptotic death trigger in target cells, so we speculate that the effect of testosterone could be mediated through both the up-regulation of N-clusterin and the down-regulation of S-clusterin.
4. This study evaluated the effect of androgen on the formation of kidney stone, the the mechanism of promotion the stone, the effect of testosterone on the renal tubular epithelial cell and the expression of clusterin in the renal tubular epithelial cell of patients with renal stone. Therefore, our study provides an important knowledge of testosterone-treated HK-2 cells in vitro and should be helpful for the further
elucidation of the molecular mechanisms involved in the interaction between androgen and renal epithelial cells and kidney stone formation, and provide new methods and for seeking effective precautionary measures for the recurrence of renal calculi.
尿石症是泌尿外科的最常见的疾病之一,而男性结石的发病率远远高于女性,以前对结石发病机制的研究多集中在动物模型中雄激素对尿液成分的影响与结石形成的关系,即尿液中草酸等促进结石成分的过饱和以及骨桥蛋白,枸橼酸等抑制结石形成的成分的减少,而近年发现仅有尿液中结石成分过饱和、抑制结石成分的下降是很难形成肾结石的,肾小管上皮细胞在肾结石产生的过程中发挥了十分重要的作用,事实上,只有结晶粘附于肾小管上皮细胞上才能继续生长,变成有临床症状的结石。但是雄激素在肾结石患者肾小管上皮细胞的作用方面,目前极少有研究涉及,而这方面的研究,能更好的阐释肾结石发病的性别差异的问题,能为肾结石的发病机制的研究提供新的研究思路和方向。
研究目的
1、探讨雄激素是否为肾结石的诱发因素之一,即雄激素是否促进了肾结石的产程。
2、探讨雄激素促进肾结石产生的机制,即雄激素对肾小管上皮细胞的作用及其作用机制。
研究内容
1、选取接受经皮肾镜检查碎石手术(PCNL术)的成年男性患者,和体检合格的正常男性患者,留取患者血浆标本采用酶联免疫法(ELISA)检测患者睾酮和游离睾酮水平；并于手术结束时超声引导下穿刺获得肾小管上皮组织；术后留取患者结石成分,采用傅立叶转换红外光谱测定结石成分。然后采用正常肾组织作为对照,采用免疫组化方法检测结石患者肾小管上皮组织的雄激素受体表达情况以及丛生蛋白的表达情况,比较二者表达与各自对照组有无差别。
2、培养HK-2细胞,然后在培养基中加入不同终浓度的睾酮(1nM、10nM、100nM、1000 nM)以及雄激素拮抗剂氟他胺(100 nM),分别作用6小时,24小时和72小时,然后采用MTT法检测睾酮对HK-2细胞的生长抑制情况,再采用流式细胞技术检测细胞的凋亡情况。
3、检测上述条件下睾酮及雄激素受体拮抗剂处理过的HK-2细胞的凋亡相关蛋白丛生蛋白的表达情况并比较其两种亚型分泌型(s-clusterin)和细胞核型(n-clusterin)表达的差别,采用RT-PCR方法和Western-blotting方法检测上述二者在mRNA水平和蛋白水平表达的差异,了解他们在睾酮诱导的肾小管上皮细胞凋亡过程中所发挥的作用。
结果
1、所有男性结石患者术后结石红外光谱测定结石成分,均以草酸钙成分为主,包括一水草酸钙和二水草酸钙。所有入选对象ELISA法检测血睾酮和游离睾酮结果表明,肾结石患者的血睾酮和游离睾酮水平均高于正常对照人群(P<0.01),而且血睾酮和游离睾酮二者具有明显的正相关关系(P<0.05)。免疫组化研究结果表明,肾小管上皮细胞的细胞核雄激素受体表达阳性,近曲小管、远曲小管、集合管均有表达,以近曲小管、远曲小管为主,而且结石患者肾组织表达强度明显高于正常对照组(P<0.05)；同样,免疫组化结果表明,在肾小管上皮细胞的细胞浆中丛生蛋白表达阳性,结石患者的表达水平高于正常对照组(P<0.05)。
2、体外HK-2细胞学实验表明,睾酮能抑制细胞增殖,MTT法检测细胞生长抑制曲线,表明随着睾酮浓度的增高,作用时间的延长,睾酮对细胞生长的抑制明显升高(P<0.01),最大的抑制率为1000nM,作用72小时；其次睾酮能诱导细胞发生凋亡,流式细胞仪检测表明,经过睾酮处理的HK-2细胞的凋亡百分率明显高于对照组细胞,而且同样随着睾酮浓度的升高、处理时间的延长,凋亡率明显升高,并且具有明显统计学意义(P<0.05)。
3、检测经睾酮处理过的HK-2细胞丛生蛋白表达情况,发现睾酮处理过以后,采用RT-PCR方法检测mRNA表达、采用western-blotting法检测蛋白水平的表达,结果发现s-clusterin蛋白表达下降,而n-clusterin蛋白表达升高,二者共同作用参与了HK-2细胞的凋亡过程。
结论
1、男性肾结石患者的血总睾酮水平、游离睾酮水平均明显高于正常对照组,肾结石肾组织的雄激素受体表达明显高于正常对照,所以推测雄激素在肾脏草酸钙结石产生过程中发挥了重要的作用,在全身循环代谢和肾脏肾小管上皮细胞都产生影响,促进了肾结石的产生。
2、睾酮能够抑制肾小管上皮细胞增殖,诱导肾小管上皮细胞发生凋亡,并且具有剂量和时间依赖效应,因此这种对肾小管上皮细胞的作用很可能是其参与肾结石形成的途径之一
3、经睾酮处理后肾小管上皮细胞,RT-PCR结果表明clusterin的mRNA水平升高,western-blotting方法检测结果表明N-clusterin的蛋白水平升高,而S-clusterin下降,我们认为二者均在肾小管上皮细胞凋亡过程中发挥重要的作用。
4、本研究对雄性激素在肾结石形成过程中的作用及其机制做了详细的研究,探讨了雄激素和雄激素受体在肾结石患者中的水平,并且进一步分析了睾酮对肾小管上皮细胞的作用以及机制,以及丛生蛋白在此过程中的作用,从而在肾小管上皮细胞损伤的方面阐释了雄激素在肾结石形成过程中的作用以及结石好发于男性的机制。
Backgrounds
The prevalence of renal stone in men was much higher than in the women, but the reason why the gender disparity exist is always unclear. Some studies had found that the urinary citrate level of females is much higher than the males. In the recent years, the study on the kidey stone is still focus on the urinary Supersaturation like calcium, oxalate, and the insufficient urinary inhibitors for formation of stone like Citrate, Osteopontin, Magnesium. Actually, in addition to urine constituents, the renal tubule epithelial cells play a role in the formation of stone. Previous studies have found that lethal renal epithelial cellular injury promotes crystal nucleation, aggregation and retention. Another study revealed that the adherence of crystals to pericellular matrixes may encompass more than their simple fixation to the polysaccharide Hyaluronan (HA). Calcium oxalate crystal retention is not prevented by coating crystals with urinary constituents such as glycoproteins and, therefore, may depend primarily on the surface properties of the renal tubular epithelium. However, the relation of the androgen and kidney stone is not still clear, and the effect of androgen on the renal tubular epithelial cell is unknown, either. Thus we speculate that perhaps androgen cytotoxic to the renal tubule epithelial cell, which induce the formation of kidney stone.
Objective
1. The purpose of this study was to determine whether testosterone would contribute to the nephrolithiasis.
2. To evaluate the effects of testosterone at different levels on human renal tubular epithelial cells (HK-2) and whether the testosterone has the effect of pro-apoptosis on the renal tubular epithelial cells
3. To evaluate the expression of clusterin in the renal tubular epithelial cell of the patients with renal stone, and identify the differently expressed proteins of two isoforms of clusterin in HK-2 cells treated with testosterone at different levels, so as to find the exact effect of the clusterin in the HK-2 cells treated with testosterone and provide new ways for further kidney stone formation.
Methods
1. Patients with renal calculi undergoing percutaneous nephrolithotomy (PCNL) were included, whose stones were analysed with a transform-infrared (FT-IR) spectrometer, but all the patients participated in this study were excluded the urinary tract infection and hydronephrosis, at the end of procedure ultrasound-guided puncture biopsy was performed to acquire the kidney tissue, while kidney tissues from autopsy archived in pathology department were obtained as the control. The expression of androgen receptor and clusterin in renal tubular epithelial cell were evaluated by immunohistochemistry. Besides this, the blood of all the subjects was collected into a tube containing 2% heparin in the morning, and the total and free serum testosterone levels were measured for each person by enzyme linked immunosorbent assay(ELISA).
2. Normal HK-2 cells were cultured in vitro and the culture medium was changed with serum-free medium after cell growth to confluence. Testosterone with different concentrations or testosterone combined flutamide were then added and the cells were incubated for 6h,24h,48h or 72h, respectively, then the ratio of cell viability was measured by MTT, while cell apoptosis was measured by annexin V/propidium iodide (PI) staining.
3. The expression two activation isoforms of clusterin were analyzed by western blotting, and the mRNA level of clusterin was measured by RT-PCR, after the HK-2 cells incubated with different levels testosterone or incubated with both testosterone and flutamide. Then the results were analyzed to clarity the function of clusterin in the apoptosis of HK-2 cell induced by testosterone.
Results
1. All the calculi included calcium oxalate monohydrate and calcium oxalate dihydrate, and a small quantity of calculi also contained the protein or uric acid. The mean serum levels of total testosterone and free testosterone in patients with kidney stone were 13.29±4.79ng/ml,28.58±4.70 pg/ml; and the levels of total testosterone, free testosterone in control group was7.30±0.82 ng/ml,24.91±4.47 pg/ml. There was significant difference of the hormones level between patients and healthy men, respectively (P<0.01). Moreover, there was a significant correlation between the total testosterone levels and free testosterone levels (r=0.824, p<0.0001). The AR expression in renal tissues was localized to cell nuclei of the renal distal tubule epithelial cell. Immunohistochemistry assessment showed up-regulation of AR in patients with kidney stones (P<0.05). Immunohistochemistry assessment showed the expression of clusterin was located in the cytoplasm of renal tubular epithelial cell, and the expression in the cells of patients was higher than in the controls significantly(P<0.05).
2. The results showed that the ratio of cell viability inhibition of HK-2 cells increased as the testosterone concentration increased and as the time increased. Maximal inhibition of proliferation was achieved after 72 h of cell exposure to testosterone 1000nM,72h, and this inhibition was time- and dose-dependent. Cells undergoing early apoptosis were usually characterized by the degree of phosphatidylserine exposure with the testosterone. HK-2 cells treated with testosterone exhibited a significant increase, which indicated that testosterone induced apoptosis in HK-2 cells in a dose- and time-dependent manner but did not cause obvious necrosis.
3. HK-2 cells treated with testosterone were analyzed by western blotting that detected the expression of clusterin. The result showed that testosterone activated the expression of N-clusterin. We also found that the down-regulation of S-clusterin in the cells exposed to testosterone, and the expression of S-clu was also shown, which was much weaker than the N-clu. The mRNA expression levels of clusterin in the HK-2 after exposure to testosterone was measured by quantitative RT-PCR.
Conclusions
1. We found both serum total testosterone and free testosterone in the male patients with renal calculi were higher in comparison with healthy men, and the expression of androgen receptor in kidney of patients was also stronger than the controls. This study indicates that total and free testosterone may play an important role in the formation of kidney calclui in male patients.
2. The HK-2 cells incubated with testosterone showed a significant dose- and time-dependent decrease in viability, and the testosterone also could induced the HK-2 to apoptosis. Therefore, the effect of pro-apoptosis on the renal tubular epithelial cell could play an important role in formation of kidney stone.
3. Our findings showed that HK-2 cell exposure to testosterone resulted in a marked accumulation of N-clusterin, which is considered an apoptotic death trigger in target cells, so we speculate that the effect of testosterone could be mediated through both the up-regulation of N-clusterin and the down-regulation of S-clusterin.
4. This study evaluated the effect of androgen on the formation of kidney stone, the the mechanism of promotion the stone, the effect of testosterone on the renal tubular epithelial cell and the expression of clusterin in the renal tubular epithelial cell of patients with renal stone. Therefore, our study provides an important knowledge of testosterone-treated HK-2 cells in vitro and should be helpful for the further
elucidation of the molecular mechanisms involved in the interaction between androgen and renal epithelial cells and kidney stone formation, and provide new methods and for seeking effective precautionary measures for the recurrence of renal calculi.
引文
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