Sonic Hedgehog信号通路对高糖诱导的肾小管上皮细胞凋亡及白藜芦醇干预作用研究
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摘要
目的：随着经济的快速发展，我国民众的生活方式有了极大的变化，糖尿病发病率逐年升高。最新研究结果显示我国总体糖尿病患病率已达9.7%，其中6.5%～42%的患者伴有肾脏病。而糖尿病肾病(diabeticnephropathy, DN)作为糖尿病最严重的并发症之一，已成为我国引发终末期肾衰竭的第二位病因。患者一旦进入终末期肾衰竭，将不得不依靠血液透析、腹膜透析或肾移植来维持生命，给国家和个人带来沉重的经济负担。因此如何有效防治糖尿病肾病是广大肾脏病学者面临的挑战，也是研究的热点问题。
既往有关糖尿病肾病的研究多集中于肾小球病变，但晚近研究表明糖尿病所致肾小管间质病变也是糖尿病肾脏病变的重要病理基础，与糖尿病肾病的进展和肾功能损害密切相关。大量研究证实，糖尿病肾小管损伤包括肾小管上皮细胞高转运、细胞的肥大以及凋亡等。细胞凋亡可导致肾小管回吸收和排秘功能失调，促进肾小管上皮细胞萎缩和肾间质纤维化。因此深入了解高糖导致的肾小管上皮细胞凋亡的机制，对探究糖尿病患者肾功能的保护具有重要意义。
哺乳动物体内有3中同源Hh基因，为Sonic hedgehog (SHH)，Indianhedgehog (IHH)和Desert hedgehog (DHH)，分别编码相应的蛋白，与器官的形成、组织的发育、细胞的分化和增殖以及损伤后的修复密切相关，并在肿瘤的发生、组织的纤维化等过程中也发挥了重要作用。研究发现，缺血再灌注肾损伤中，Shh信号通路与肾功能损害密切相关，并且该信号通路可以诱导梗阻性肾病大鼠肾小管上皮细胞转分化。提示Hh信号通路不仅在控制胚胎发育，而且在胚胎发育完成后依然调控着细胞的生长、增殖和分化过程，参与了体内多种生物学行为。
虽然对糖尿病并发症的研究越来越深入，但是尚无防治糖尿病肾病的有效手段。目前主要是血管紧张素转换酶抑制剂和/或血管紧张素受体拮抗剂的应用，以及控制血糖、调整血脂等综合治疗。白藜芦醇(Resveratrol)化学名称为芪三酚，广泛存在于葡萄科、百合科、寥科等70种植物中，在我国的传统中药虎杖和何首乌等中也发现有其存在。该药具有抑制血小板聚集、调节脂代谢、抗菌、抗癌、抗衰老等作用，能够通过抗氧化应激保护db/db鼠的肾脏。体外实验也表明白藜芦醇能抑制肾脏系膜细胞的增殖，影响细胞周期的分布，但其对糖尿病肾病肾脏保护的确切机制仍不明确。
本研究拟通过临床观察、细胞培养和动物实验，全面分析Shh及其信号通路相关蛋白Ptch (Patched)、Smo(Smoothened)、Gli2(Glioma-associatedoncogenes2)在高糖状态下肾组织中的表达变化，以及该信号通路与肾小管上皮细胞凋亡的关系。利用siRNA转染技术，测定在体外干扰高糖环境培养的人肾小管上皮细胞系(HK-2细胞)转录合成Shh后，肾小管上皮细胞发生凋亡的情况。并给予含有重组Shh蛋白的培养基培养HK-2细胞，进一步明确Shh信号通路在调控细胞凋亡中发挥的作用。通过对STZ诱导的糖尿病小鼠和高糖环境中培养的HK-2细胞给予白藜芦醇进行干预，从转录和分子水平观察白藜芦醇对Shh信号通路的影响及其发挥肾脏保护作用的可能途径，为进一步阐明糖尿病状态下肾小管上皮细胞凋亡发生的分子学机制及防治提供实验性依据。
方法：
第一部分：从我院肾内科2010年6月至2012年6月住院患者中选择符合1999年WHO2型糖尿病诊断标准并经肾活检病理检查确诊为糖尿病肾病的12例患者为研究对象，另外5例正常肾组织（选自我院泌尿外科肾癌患者手术切除的肾脏病灶远周部分）作为正常对照组，进行免疫组织化学染色，半定量分析各组肾组织标本中Shh信号通路相关蛋白Shh、Ptch1、Smo、Gli2的表达；TUNEL检测肾小管上皮细胞的凋亡。
第二部分：体外培养人肾小管上皮细胞系(HK-2细胞)，分为3组，低糖组、高糖组和甘露醇组。同步化12小时后给予相应的刺激，于刺激后12h、24h、48h、72h，消化收集各组细胞，75%乙醇固定，送流式检测凋亡细胞百分比。
体外培养的HK-2细胞，以细胞凋亡最明显的时间为干预时间，以低糖和高糖组为对照，分别应用重组人Shh蛋白、白藜芦醇干预或者进行Shh siRNA转染，同步化12小时后给予相应的刺激，届时收集各组细胞，提取细胞总蛋白、总RNA，应用western blot测定各组细胞Shh、Ptch1、Smo、Gli2、p53、Bax和cleaved caspase3蛋白的表达，real time PCR检测Shh、Gli2mRNA的表达。同时消化离心细胞，75%乙醇固定，送流式检测凋亡细胞百分比。另外铺六孔板，共聚焦显微镜检测Shh、Ptch1、Smo、Gli2在细胞中的表达，TUNEL观察细胞凋亡情况。
第三部分：建立单侧肾切除+链脲佐菌素诱导的CD-1小鼠(体重20g±2g)1型糖尿病模型，设立单纯单侧肾切除组(对照组，n=24)、单侧肾切除+糖尿病组(模型组，n=24)，单侧肾切除+糖尿病+白藜芦醇干预组(干预组，n=24)实验共24周，分别于第8、12和24周末收集各组小鼠血、尿和肾组织标本，测定血糖(blood glucose, BG)、血肌酐(serum creatinine,Scr)、血清总胆固醇(total cholesterol, TC)、甘油三酯(triglyceride, TG)、尿蛋白(urinary protein, UP)，并计算肾重/体重比值(kidney weight/body weightratio, KW/BW)。肾组织行苏木素-伊红(ematoxylin-eosin, HE)染色和过碘酸-希夫(periodic acid-schiff, PAS)染色，普通光镜下观察肾组织病理学改变。应用免疫组织化学染色检测肾组织Shh、Ptch1、Smo、Gli2的表达；westernblot检测Shh、Ptch1、Smo、Gli2以及凋亡相关蛋白p53、Bax、cleaved caspase3的表达；real time PCR测定肾组织Shh、Gli2mRNA的表达；TUNAL观察肾小管上皮细胞的凋亡。
结果：
第一部分：正常肾组织中有Shh、Ptch1、Smo及Gli2的表达，以肾小管为主，肾小球几乎无表达。在糖尿病肾病患者肾组织切片中，上述4种蛋白表达较正常组减弱，差异有统计学意义(p＜0.05)。肾组织石蜡切片TUNEL检测，糖尿病肾病组肾小管上皮细胞凋亡数量明显高于对照组，差异有统计学意义(p＜0.05)。
第二部分：在高糖刺激48小时，HK-2细胞凋亡达高峰，凋亡细胞百分比较其他3个时间点，即12h、24h、72h明显升高，差异有统计学意义(p＜0.05)。Western blot结果显示，48小时高糖组Shh、Ptch1、Smo和Gli2蛋白表达均较低糖组、甘露醇组明显降低，差异有统计学意义(p＜0.05)；p53、Bax、cleaved caspase3表达则明显高于低糖组和甘露醇组，差异有统计学意义(p＜0.05)；高糖组Shh、Gli2mRNA表达也明显下降，低于低糖组和甘露醇组，差异有统计学意义(p＜0.05)。
HK-2细胞转染Shh siRNA后培养48h，高糖转染Shh siRNA组(HG+siShh组)细胞凋亡率最高，与低糖组、高糖组、高糖转染无关对照组(HG+siCon组)相比，差异有统计学意义(p＜0.05)；Shh、Ptch1、Smo和Gli2表达较其他各组降低，p53、Bax、cleaved caspase3表达较其他各组升高明显，Shh、Gli2mRNA表达低于其他各组，差异有统计学意义(p＜0.05)。高糖组和HG+siCon组之间上述各指标无明显统计学差异(p＞0.05)。
高糖培养的HK-2细胞加入重组人Shh蛋白刺激48h后，细胞凋亡发生率较高糖组明显降低，差异有统计学意义(p＜0.05)；Shh、Ptch1、Smo和Gli2表达较高糖组升高，p53、Bax、cleaved caspase3表达明显低于高糖组，差异有统计学意义(p＜0.05)； Gli2mRNA表达也明显高于高糖组，差异有统计学意义(p＜0.05)。
对HK-2细胞给予高糖联合白藜芦醇刺激48h，细胞凋亡较高糖组减少，p53、Bax、cleaved caspase3表达明显降低，差异有统计学意义(p＜0.05)； Shh、Ptch1、Smo、Gli2及Shh、Gli2mRNA表达也明显上调，高于高糖组，差异有统计学意义(p＜0.05)。
第三部分：小鼠注射STZ后3天左右即出现多饮、多食、多尿等糖尿病症状；第8周末，模型组小鼠肾小管间质有少量淋巴单核细胞浸润。随着病程进展，12周末和24周末小鼠肾组织病变加重，小管间质淋巴单核细胞浸润增多，小管上皮细胞出现绒毛脱落，小管扩张，肾小球系膜区增宽等，而对照组无明显病变，干预组病变介于对照组和模型组之间。与对照组相比，模型组和干预组小鼠在8周、12周，24周末时血糖明显增高，差异有统计学意义(p＜0.05)；但三组小鼠血胆固醇和甘油三酯无统计学差异(p＞0.05)；12周、24周末时，模型组和干预组出现肾重/体重比增加，以及血肌酐和蛋白尿的升高，与对照组比较，差异有统计学意义(p＜0.05)。自12周末起，模型组小鼠肾组织匀浆Shh、Ptch1、Smo、Gli2表达下降，Shh、Gli2mRNA表达减弱，与对照组相比，差异有统计学意义(p＜0.05)；自8周末起，模型组小鼠肾组织匀浆p53、Bax、cleaved caspase3表达明显增强，与对照组相比，差异有统计学意义(p＜0.05)；干预组上述指标介于对照组和模型组之间，三组间差异有统计学意义(p＜0.05)。TUNEL结果证实，模型组在12周、24周末肾小管上皮细胞凋亡数目增加，干预组细胞凋亡减少，但仍多于对照组，三组间结果差异有统计学意义(p＜0.05)。
结论：
1本研究结果显示，Shh在成年人或小鼠肾脏内有基础表达，主要分布于肾小管上皮细胞。但在糖尿病肾病状态下Shh及其信号通路相关蛋白Ptch1、Smo、Gli2在肾小管上皮细胞中表达明显减弱。
2体外实验证实，以siRNA干扰HK-2细胞中Shh基因的合成能够抑制Shh信号的传递，抑制核转录因子Gli2的表达，从而使其下游靶基因的转录表达减弱，进一步上调凋亡相关基因p53、Bax的表达，诱导caspase3的活化，发挥促进细胞凋亡的作用，提示Shh信号通路参与了高糖诱导的肾小管上皮细胞凋亡，此过程与凋亡基因的p53、Bax有关。
3在体外给予重组Shh刺激HK-2细胞后，可明显活化Shh信号通路，促进Gli2基因及其蛋白的表达，抑制凋亡相关基因p53、Bax的表达，干扰caspase3的活化，发挥抑制细胞凋亡的作用。提示上调Shh信号通路能够抑制高糖诱导的肾小管上皮细胞的凋亡。
4体外和体内的研究表明，白藜芦醇可以从基因水平和蛋白水平调节Shh及其下游Ptch1、Smo、Gli2的表达，进而抑制p53、Bax和caspase3的表达，从而减轻高糖诱导的肾小管上皮细胞的凋亡，具有肾脏保护作用，可能是临床防治糖尿病肾病的一个新方法。
Objective: With the rapid development of economy, human’s lifestyleshave some dramatic changes and the incidence of diabetes is increasing.Current data shows that the incidence of diabetes gets to9.7%and6.5%～42%of diabetics accompanies with diabetic nephropathy. Therefore, diabeticnephropathy has become the second reason for end-stage renal failure in China.Once in the end-stage renal failure stage, patients will have to depend onhemodialysis, peritoneal dialysis or kidney transplantation to sustainlife.Those treatment cost should provide a huge economic burden to societyand family. Thus, it is the effective prevention and treatment of diabeticnephropathy that is a topic issue and a huge challenge in the world.
In past studies about diabetic nephropathy, most of which ever focusedon glomerular pathological changes. The renal tubulointerstitial lesions whichderive from diabetic nephropathy are not only pathological basis of renaldisease, but also closely related to renal damage and the progress of diabeticnephropathy. In many studies, it had been confirmed that apoptosis of renaltubular epithelial cells happened in early stage of diabetic nephropathy, whichinduced dysfunction function of reabsorption and excretion and ultimatelylead to tubular atrophy and interstitial fibrosis. Thus, it is significant tounderstand the high glucose induced apoptosis of renal tubular epithelial cellsin order to protect renal function in patients with diabetes.
There were three homologous Hh gene in Mammals, and encoded Sonichedgehog (Shh), Indian hedgehog (IHH) and Desert hedgehog (DHH),respectively. They did not only closely relate to organic formation, tissuedevelopment, cell differentiation and proliferation and repair after injury, butplay an important role in the process of tumorigenesis and tissue fibrosis.Recent studies showed that Shh signaling pathway related to damage of the renal function in ischemia reperfusion renal injury, and it also inducedepithelial-to-mesenchymal transition (EMT) in obstructive nephropathy.Hence, Hh signaling pathway involved in a variety of biological behavior invivo, such as controlling of embryonic development, regulated cell growth,proliferation and differentiation process after embryos had completed thedevelopment.
Although, there are more and more pathogenesis and therapeuticmethod study for diabetic nephropathy, but effectively therapeutic method fordiabetic nephropathy haven’t been founded by now. Resveratrol is known as astilbene phenols and widely present in70species of plants, such as grapes,Liliaceae, Polygonaceae. It was also found in Chinese traditional medicine,such as Polygonum cuspidatum, Polygonum and so on. Resveratrol couldinhibit platelet aggregation, regulate the role of lipid metabolism,anti-bacterial, anti-cancer, anti-aging, and it also can protect db-/db-mousekidney through anti-oxidative stress. It is showed that resveratrol can inhibitmesangialcell proliferation, influence cell cycle in vitro. However, themechanisms which protect the kidney of diabetic nephropathy is still unclear.In this study, whether Shh signaling pathway involved in apoptosis of renaltubular epithelial cell which induced by high glucose were explored, then theprotein expression of Shh signaling pathway in renal tissue of diabetic statehad been observed in vivo and vitro. To further investigate the effects of shhsignaling pathway on apoptosis in high glucose induced HK-2cells, wesuppress or enhance shh by transfected Shh siRNA or incubated HK-2cellswith recombinant human Shh protein. Finally, in order to clarify whetherresveratrol protect the kidney via the shh signalling pathway, we culturedHK-2cells with high glucose and resveratrol,established diabetic mice by STZ,then analyzed the change of shh signalling pathway.
Methods:
Part1:12diabetic nephropathy patients in line with the diagnosticcriteria for type2diabetes of American Diabetes Academy in1999wereconfirmed by renal biopsy from the department of nephrology in3rd hospital of Hebei Medical Universty (HBMU) from June2006to June2007.5healthcases were received from the normal tissues around the resected renal tumorsof hospitalized patients in3rd hospital of HBMU. The expression of Shh,Ptch1, Smo and Gli2in renal tissue of every group was semi-quantitativelyanalysed by immunohistochemical staining. The apoptosis of renal tubularepithelial cells were detected by TUNEL staining. The expression of Shh,Ptch1, Smo and Gli2in renal tissue of every group were detected byimmunohistochemical staining and the apoptosis of renal tubular epithelialcells were detected by TUNEL staining were analysed by semi-quantitatively.
Part2: HK-2cells were grown in in non-glucose DMEM mixed withDMEM F12containing10%FBS, penicillin (100U/ml), streptomycin (100μg/ml) at37°C and5%CO2. The cells were divided into3groups, a lowglucose group (5.8mmol/L glucose, LG), a high glucose group (30mmol/Lglucose, HG), and low glucose mixed with mannitol group (5.8mmol/Lglucose mixed with24.2mM mannitol, M) after synchronizated in12hours,then the cells were collected at12h,24h,48h and72h for the determination ofthe percentage of apoptotic cells with flow cytometry.
Next, Western blot was used to detect the expression of Shh, Ptch1, Smo,Gli2, p53, Bax, and cleaved caspase3protein expression level, and real timePCR was used to detect the mRNA expression level of Shh, Gli2in HK-2cells,which incubated with high glucose and recombinant human Shh protein, orresveratrol, or transfected Shh siRNA after the time of apoptosis significantly.Meanwhile, the percentage of cells apoptosis was detected by flow cytometryand the expression of Shh, Ptch1, Smo and Gli2were detected byimmunofluorescence. All of the data was analysed by SPSS15.0statisticssoftware, P value<0.05was considered as statistical significance.
Part3: The male CD-1mice(weight about20+/-2g) were divided intothree groups: a simple unilateral renal resection group (control group, n=24), asimple unilateral renal resection and injection of streptozotocin induceddiabetes group (model group, n=24), and a simple unilateral renal resectionand injection of streptozotocin induced diabetes treated with resveratrol group(treatment group, n=24). The animals of model and treatment groupswere received a single intravenous dose of130mg/kg streptozotocin in citratebuffer to induce diabetes. NC group were received the same dose of citratebuffer. Hyperglycemia (＞16.7mmol/L) was confirmed3days after STZadministration.
The animals were sacrificed at8week,12week and24week. The urineand blood samples were collected, and kidney tissues were harvested at8,12,24weekend. Kidney tissues were fixed in4%paraformaldehyde andembedded in paraffin for light microscopy and immunohistochemistry. Theparaformaldehyde-fixed and paraffin-embedded kidney tissues were cut intosections of4μm thick for stained with matoxylin-eosin (HE), periodicacid-schiff (PAS), immunohistochemistry and TUNEL staining. HE and PASstaining were used to observe the pathological changes.Immunohistochemistry was used to analyze the renal expression of Shh, Ptch1,Smo and Gli2. BG, serum creatinine (Scr), serum total cholesterol (TC),triglyceride (TG), urine protein (Ucr), and hypertrophy index (the ratio ofkidney weight: body weight) were evaluated in every group. The apoptosis ofrenal tubular epithelial cells were stained by TUNEL. The protein level of Shh,Ptch1, Smo, Gli2, P53, Bax, cleaved caspase-3were detected by western blotand the level of mRNA for Shh and Gli2were detected by real time PCR. Allthe data were analysed by SPSS15.0statistics software, P value＜0.05wasconsidered to have statistical significance.
Result:
Part1: Compare to normal tissue, the expression of shh, Ptch1, Smo andGli2decreased and apoptosis increased in diabetic nephropathy. There was asignificant difference between normal and diabetic nephropathy group (p＜0.05).
Part2: In vitro, the apoptosis of HK-2cells reached a peak in48hoursafter incubated with high glucose compare to12h,24h and72h (p＜0.05).Western blot analyzed the expression of protein level found that Shh, Ptch1,Smo, Gli2were declined and p53、Bax、cleaved caspase3were rised when high glucose induced for48h (p＜0.05) as well as mRNA of Shh and Gli2alsoincreased (p＜0.05).
After cells were transfected with Shh siRNA, the percentage of apoptosisin HK-2cells was higher than non-transfection group, and the levels of Shh,Ptch1, Smo, Gli2protein were higher, which have statistical significance whencompared with HG group.The expression of p53, Bax and cleaved caspase3were higher in transfection group than non-transfecting (p＜0.05).
Stimulated HK-2cells with recombinant human Shh protein, theapoptosis rate decreased, and p53, Bax and cleaved caspase3expression wassignificantly lower than HG group (p＜0.05). But the protein levels of Shh,Ptch1, Smo, Gli2and mRNA level of Gli2were significantly up-regulated (p＜0.05).
When stimulated HK-2cells with resveratrol, result in the apoptosis rateand p53, Bax and cleaved caspase3expression were lower than HG group (p＜0.05), and the protein levels of Shh, Ptch1, Smo, Gli2and mRNA levels ofShh, Gli2were significantly up-regulated (p＜0.05).
Part3: Polydipsia, polyphagia and polyuria of diabetic symptoms wereappeared after the mice were injected with STZ for about3days. There were asmall amount of lymphoid mononuclear cell infiltration in tubulointerstitialafter injected STZ for8weeks, and it was found that a large amount oflymphoid mononuclear cell infiltration in the tubules, tubular epithelial cellsof the fluff off, tubular dilatation when STZ injected for12weeks and24weeks. However, there were no significantly lesions in glomerular mesangialcompared to control group and model group.
At week-12, Scr and KW/BW ratio are the lowest in the control group,the highest in the model group, followed by treatment group, there aresignificant differences among the three groups (p＜0.05). Compared withmodel group, the levels of Shh, Ptch1, Smo and Gli2and mRNA of Shh andGli2were upregualted and p53, Bax and cleaved caspase3weredownregulated in treatment group (p＜0.05). The apoptosis of renal tubularepithelial cells in treatment group was higher than control group, but lower than model group (p＜0.05).
Conclusions:
1There was basic expression of Shh signaling pathway in normal humanrenal tissues, but Shh signaling pathway was inhibited in renal tubularepithelial cells of diabete.
2In HK-2, interfered Shh gene expression by siRNA, which can inducethe activation of caspase3and increase the expression of p53and Bax, andpromote apoptosis. It is suggested that Shh signaling pathway might involvedin the apoptosis of HK-2cells, which reduced by high glucose.
3The expression of p53, Bax and caspase3were decreased when addedrecombinant human Shh protein to activate Shh pathway in HK-2, it is showedthat Shh can inhibit apoptosis of tubular cells which were stimulated with highglucose. Which provide a new idea for prevention and treatment of diabeticnephropathy.
4The date shown that resveratrol can adjusted Shh, Ptch1, Smo and Gli2expression by gene and protein levels, and then regulated p53, Bax andcaspase3expression, thereby inhibiting high glucose-induced apoptosis ofrenal tubular epithelial cells. Therefore, resveratrol may be a novel materialfor the prevention and treatment of diabetic nephropathy.
既往有关糖尿病肾病的研究多集中于肾小球病变，但晚近研究表明糖尿病所致肾小管间质病变也是糖尿病肾脏病变的重要病理基础，与糖尿病肾病的进展和肾功能损害密切相关。大量研究证实，糖尿病肾小管损伤包括肾小管上皮细胞高转运、细胞的肥大以及凋亡等。细胞凋亡可导致肾小管回吸收和排秘功能失调，促进肾小管上皮细胞萎缩和肾间质纤维化。因此深入了解高糖导致的肾小管上皮细胞凋亡的机制，对探究糖尿病患者肾功能的保护具有重要意义。
哺乳动物体内有3中同源Hh基因，为Sonic hedgehog (SHH)，Indianhedgehog (IHH)和Desert hedgehog (DHH)，分别编码相应的蛋白，与器官的形成、组织的发育、细胞的分化和增殖以及损伤后的修复密切相关，并在肿瘤的发生、组织的纤维化等过程中也发挥了重要作用。研究发现，缺血再灌注肾损伤中，Shh信号通路与肾功能损害密切相关，并且该信号通路可以诱导梗阻性肾病大鼠肾小管上皮细胞转分化。提示Hh信号通路不仅在控制胚胎发育，而且在胚胎发育完成后依然调控着细胞的生长、增殖和分化过程，参与了体内多种生物学行为。
虽然对糖尿病并发症的研究越来越深入，但是尚无防治糖尿病肾病的有效手段。目前主要是血管紧张素转换酶抑制剂和/或血管紧张素受体拮抗剂的应用，以及控制血糖、调整血脂等综合治疗。白藜芦醇(Resveratrol)化学名称为芪三酚，广泛存在于葡萄科、百合科、寥科等70种植物中，在我国的传统中药虎杖和何首乌等中也发现有其存在。该药具有抑制血小板聚集、调节脂代谢、抗菌、抗癌、抗衰老等作用，能够通过抗氧化应激保护db/db鼠的肾脏。体外实验也表明白藜芦醇能抑制肾脏系膜细胞的增殖，影响细胞周期的分布，但其对糖尿病肾病肾脏保护的确切机制仍不明确。
本研究拟通过临床观察、细胞培养和动物实验，全面分析Shh及其信号通路相关蛋白Ptch (Patched)、Smo(Smoothened)、Gli2(Glioma-associatedoncogenes2)在高糖状态下肾组织中的表达变化，以及该信号通路与肾小管上皮细胞凋亡的关系。利用siRNA转染技术，测定在体外干扰高糖环境培养的人肾小管上皮细胞系(HK-2细胞)转录合成Shh后，肾小管上皮细胞发生凋亡的情况。并给予含有重组Shh蛋白的培养基培养HK-2细胞，进一步明确Shh信号通路在调控细胞凋亡中发挥的作用。通过对STZ诱导的糖尿病小鼠和高糖环境中培养的HK-2细胞给予白藜芦醇进行干预，从转录和分子水平观察白藜芦醇对Shh信号通路的影响及其发挥肾脏保护作用的可能途径，为进一步阐明糖尿病状态下肾小管上皮细胞凋亡发生的分子学机制及防治提供实验性依据。
方法：
第一部分：从我院肾内科2010年6月至2012年6月住院患者中选择符合1999年WHO2型糖尿病诊断标准并经肾活检病理检查确诊为糖尿病肾病的12例患者为研究对象，另外5例正常肾组织（选自我院泌尿外科肾癌患者手术切除的肾脏病灶远周部分）作为正常对照组，进行免疫组织化学染色，半定量分析各组肾组织标本中Shh信号通路相关蛋白Shh、Ptch1、Smo、Gli2的表达；TUNEL检测肾小管上皮细胞的凋亡。
第二部分：体外培养人肾小管上皮细胞系(HK-2细胞)，分为3组，低糖组、高糖组和甘露醇组。同步化12小时后给予相应的刺激，于刺激后12h、24h、48h、72h，消化收集各组细胞，75%乙醇固定，送流式检测凋亡细胞百分比。
体外培养的HK-2细胞，以细胞凋亡最明显的时间为干预时间，以低糖和高糖组为对照，分别应用重组人Shh蛋白、白藜芦醇干预或者进行Shh siRNA转染，同步化12小时后给予相应的刺激，届时收集各组细胞，提取细胞总蛋白、总RNA，应用western blot测定各组细胞Shh、Ptch1、Smo、Gli2、p53、Bax和cleaved caspase3蛋白的表达，real time PCR检测Shh、Gli2mRNA的表达。同时消化离心细胞，75%乙醇固定，送流式检测凋亡细胞百分比。另外铺六孔板，共聚焦显微镜检测Shh、Ptch1、Smo、Gli2在细胞中的表达，TUNEL观察细胞凋亡情况。
第三部分：建立单侧肾切除+链脲佐菌素诱导的CD-1小鼠(体重20g±2g)1型糖尿病模型，设立单纯单侧肾切除组(对照组，n=24)、单侧肾切除+糖尿病组(模型组，n=24)，单侧肾切除+糖尿病+白藜芦醇干预组(干预组，n=24)实验共24周，分别于第8、12和24周末收集各组小鼠血、尿和肾组织标本，测定血糖(blood glucose, BG)、血肌酐(serum creatinine,Scr)、血清总胆固醇(total cholesterol, TC)、甘油三酯(triglyceride, TG)、尿蛋白(urinary protein, UP)，并计算肾重/体重比值(kidney weight/body weightratio, KW/BW)。肾组织行苏木素-伊红(ematoxylin-eosin, HE)染色和过碘酸-希夫(periodic acid-schiff, PAS)染色，普通光镜下观察肾组织病理学改变。应用免疫组织化学染色检测肾组织Shh、Ptch1、Smo、Gli2的表达；westernblot检测Shh、Ptch1、Smo、Gli2以及凋亡相关蛋白p53、Bax、cleaved caspase3的表达；real time PCR测定肾组织Shh、Gli2mRNA的表达；TUNAL观察肾小管上皮细胞的凋亡。
结果：
第一部分：正常肾组织中有Shh、Ptch1、Smo及Gli2的表达，以肾小管为主，肾小球几乎无表达。在糖尿病肾病患者肾组织切片中，上述4种蛋白表达较正常组减弱，差异有统计学意义(p＜0.05)。肾组织石蜡切片TUNEL检测，糖尿病肾病组肾小管上皮细胞凋亡数量明显高于对照组，差异有统计学意义(p＜0.05)。
第二部分：在高糖刺激48小时，HK-2细胞凋亡达高峰，凋亡细胞百分比较其他3个时间点，即12h、24h、72h明显升高，差异有统计学意义(p＜0.05)。Western blot结果显示，48小时高糖组Shh、Ptch1、Smo和Gli2蛋白表达均较低糖组、甘露醇组明显降低，差异有统计学意义(p＜0.05)；p53、Bax、cleaved caspase3表达则明显高于低糖组和甘露醇组，差异有统计学意义(p＜0.05)；高糖组Shh、Gli2mRNA表达也明显下降，低于低糖组和甘露醇组，差异有统计学意义(p＜0.05)。
HK-2细胞转染Shh siRNA后培养48h，高糖转染Shh siRNA组(HG+siShh组)细胞凋亡率最高，与低糖组、高糖组、高糖转染无关对照组(HG+siCon组)相比，差异有统计学意义(p＜0.05)；Shh、Ptch1、Smo和Gli2表达较其他各组降低，p53、Bax、cleaved caspase3表达较其他各组升高明显，Shh、Gli2mRNA表达低于其他各组，差异有统计学意义(p＜0.05)。高糖组和HG+siCon组之间上述各指标无明显统计学差异(p＞0.05)。
高糖培养的HK-2细胞加入重组人Shh蛋白刺激48h后，细胞凋亡发生率较高糖组明显降低，差异有统计学意义(p＜0.05)；Shh、Ptch1、Smo和Gli2表达较高糖组升高，p53、Bax、cleaved caspase3表达明显低于高糖组，差异有统计学意义(p＜0.05)； Gli2mRNA表达也明显高于高糖组，差异有统计学意义(p＜0.05)。
对HK-2细胞给予高糖联合白藜芦醇刺激48h，细胞凋亡较高糖组减少，p53、Bax、cleaved caspase3表达明显降低，差异有统计学意义(p＜0.05)； Shh、Ptch1、Smo、Gli2及Shh、Gli2mRNA表达也明显上调，高于高糖组，差异有统计学意义(p＜0.05)。
第三部分：小鼠注射STZ后3天左右即出现多饮、多食、多尿等糖尿病症状；第8周末，模型组小鼠肾小管间质有少量淋巴单核细胞浸润。随着病程进展，12周末和24周末小鼠肾组织病变加重，小管间质淋巴单核细胞浸润增多，小管上皮细胞出现绒毛脱落，小管扩张，肾小球系膜区增宽等，而对照组无明显病变，干预组病变介于对照组和模型组之间。与对照组相比，模型组和干预组小鼠在8周、12周，24周末时血糖明显增高，差异有统计学意义(p＜0.05)；但三组小鼠血胆固醇和甘油三酯无统计学差异(p＞0.05)；12周、24周末时，模型组和干预组出现肾重/体重比增加，以及血肌酐和蛋白尿的升高，与对照组比较，差异有统计学意义(p＜0.05)。自12周末起，模型组小鼠肾组织匀浆Shh、Ptch1、Smo、Gli2表达下降，Shh、Gli2mRNA表达减弱，与对照组相比，差异有统计学意义(p＜0.05)；自8周末起，模型组小鼠肾组织匀浆p53、Bax、cleaved caspase3表达明显增强，与对照组相比，差异有统计学意义(p＜0.05)；干预组上述指标介于对照组和模型组之间，三组间差异有统计学意义(p＜0.05)。TUNEL结果证实，模型组在12周、24周末肾小管上皮细胞凋亡数目增加，干预组细胞凋亡减少，但仍多于对照组，三组间结果差异有统计学意义(p＜0.05)。
结论：
1本研究结果显示，Shh在成年人或小鼠肾脏内有基础表达，主要分布于肾小管上皮细胞。但在糖尿病肾病状态下Shh及其信号通路相关蛋白Ptch1、Smo、Gli2在肾小管上皮细胞中表达明显减弱。
2体外实验证实，以siRNA干扰HK-2细胞中Shh基因的合成能够抑制Shh信号的传递，抑制核转录因子Gli2的表达，从而使其下游靶基因的转录表达减弱，进一步上调凋亡相关基因p53、Bax的表达，诱导caspase3的活化，发挥促进细胞凋亡的作用，提示Shh信号通路参与了高糖诱导的肾小管上皮细胞凋亡，此过程与凋亡基因的p53、Bax有关。
3在体外给予重组Shh刺激HK-2细胞后，可明显活化Shh信号通路，促进Gli2基因及其蛋白的表达，抑制凋亡相关基因p53、Bax的表达，干扰caspase3的活化，发挥抑制细胞凋亡的作用。提示上调Shh信号通路能够抑制高糖诱导的肾小管上皮细胞的凋亡。
4体外和体内的研究表明，白藜芦醇可以从基因水平和蛋白水平调节Shh及其下游Ptch1、Smo、Gli2的表达，进而抑制p53、Bax和caspase3的表达，从而减轻高糖诱导的肾小管上皮细胞的凋亡，具有肾脏保护作用，可能是临床防治糖尿病肾病的一个新方法。
Objective: With the rapid development of economy, human’s lifestyleshave some dramatic changes and the incidence of diabetes is increasing.Current data shows that the incidence of diabetes gets to9.7%and6.5%～42%of diabetics accompanies with diabetic nephropathy. Therefore, diabeticnephropathy has become the second reason for end-stage renal failure in China.Once in the end-stage renal failure stage, patients will have to depend onhemodialysis, peritoneal dialysis or kidney transplantation to sustainlife.Those treatment cost should provide a huge economic burden to societyand family. Thus, it is the effective prevention and treatment of diabeticnephropathy that is a topic issue and a huge challenge in the world.
In past studies about diabetic nephropathy, most of which ever focusedon glomerular pathological changes. The renal tubulointerstitial lesions whichderive from diabetic nephropathy are not only pathological basis of renaldisease, but also closely related to renal damage and the progress of diabeticnephropathy. In many studies, it had been confirmed that apoptosis of renaltubular epithelial cells happened in early stage of diabetic nephropathy, whichinduced dysfunction function of reabsorption and excretion and ultimatelylead to tubular atrophy and interstitial fibrosis. Thus, it is significant tounderstand the high glucose induced apoptosis of renal tubular epithelial cellsin order to protect renal function in patients with diabetes.
There were three homologous Hh gene in Mammals, and encoded Sonichedgehog (Shh), Indian hedgehog (IHH) and Desert hedgehog (DHH),respectively. They did not only closely relate to organic formation, tissuedevelopment, cell differentiation and proliferation and repair after injury, butplay an important role in the process of tumorigenesis and tissue fibrosis.Recent studies showed that Shh signaling pathway related to damage of the renal function in ischemia reperfusion renal injury, and it also inducedepithelial-to-mesenchymal transition (EMT) in obstructive nephropathy.Hence, Hh signaling pathway involved in a variety of biological behavior invivo, such as controlling of embryonic development, regulated cell growth,proliferation and differentiation process after embryos had completed thedevelopment.
Although, there are more and more pathogenesis and therapeuticmethod study for diabetic nephropathy, but effectively therapeutic method fordiabetic nephropathy haven’t been founded by now. Resveratrol is known as astilbene phenols and widely present in70species of plants, such as grapes,Liliaceae, Polygonaceae. It was also found in Chinese traditional medicine,such as Polygonum cuspidatum, Polygonum and so on. Resveratrol couldinhibit platelet aggregation, regulate the role of lipid metabolism,anti-bacterial, anti-cancer, anti-aging, and it also can protect db-/db-mousekidney through anti-oxidative stress. It is showed that resveratrol can inhibitmesangialcell proliferation, influence cell cycle in vitro. However, themechanisms which protect the kidney of diabetic nephropathy is still unclear.In this study, whether Shh signaling pathway involved in apoptosis of renaltubular epithelial cell which induced by high glucose were explored, then theprotein expression of Shh signaling pathway in renal tissue of diabetic statehad been observed in vivo and vitro. To further investigate the effects of shhsignaling pathway on apoptosis in high glucose induced HK-2cells, wesuppress or enhance shh by transfected Shh siRNA or incubated HK-2cellswith recombinant human Shh protein. Finally, in order to clarify whetherresveratrol protect the kidney via the shh signalling pathway, we culturedHK-2cells with high glucose and resveratrol,established diabetic mice by STZ,then analyzed the change of shh signalling pathway.
Methods:
Part1:12diabetic nephropathy patients in line with the diagnosticcriteria for type2diabetes of American Diabetes Academy in1999wereconfirmed by renal biopsy from the department of nephrology in3rd hospital of Hebei Medical Universty (HBMU) from June2006to June2007.5healthcases were received from the normal tissues around the resected renal tumorsof hospitalized patients in3rd hospital of HBMU. The expression of Shh,Ptch1, Smo and Gli2in renal tissue of every group was semi-quantitativelyanalysed by immunohistochemical staining. The apoptosis of renal tubularepithelial cells were detected by TUNEL staining. The expression of Shh,Ptch1, Smo and Gli2in renal tissue of every group were detected byimmunohistochemical staining and the apoptosis of renal tubular epithelialcells were detected by TUNEL staining were analysed by semi-quantitatively.
Part2: HK-2cells were grown in in non-glucose DMEM mixed withDMEM F12containing10%FBS, penicillin (100U/ml), streptomycin (100μg/ml) at37°C and5%CO2. The cells were divided into3groups, a lowglucose group (5.8mmol/L glucose, LG), a high glucose group (30mmol/Lglucose, HG), and low glucose mixed with mannitol group (5.8mmol/Lglucose mixed with24.2mM mannitol, M) after synchronizated in12hours,then the cells were collected at12h,24h,48h and72h for the determination ofthe percentage of apoptotic cells with flow cytometry.
Next, Western blot was used to detect the expression of Shh, Ptch1, Smo,Gli2, p53, Bax, and cleaved caspase3protein expression level, and real timePCR was used to detect the mRNA expression level of Shh, Gli2in HK-2cells,which incubated with high glucose and recombinant human Shh protein, orresveratrol, or transfected Shh siRNA after the time of apoptosis significantly.Meanwhile, the percentage of cells apoptosis was detected by flow cytometryand the expression of Shh, Ptch1, Smo and Gli2were detected byimmunofluorescence. All of the data was analysed by SPSS15.0statisticssoftware, P value<0.05was considered as statistical significance.
Part3: The male CD-1mice(weight about20+/-2g) were divided intothree groups: a simple unilateral renal resection group (control group, n=24), asimple unilateral renal resection and injection of streptozotocin induceddiabetes group (model group, n=24), and a simple unilateral renal resectionand injection of streptozotocin induced diabetes treated with resveratrol group(treatment group, n=24). The animals of model and treatment groupswere received a single intravenous dose of130mg/kg streptozotocin in citratebuffer to induce diabetes. NC group were received the same dose of citratebuffer. Hyperglycemia (＞16.7mmol/L) was confirmed3days after STZadministration.
The animals were sacrificed at8week,12week and24week. The urineand blood samples were collected, and kidney tissues were harvested at8,12,24weekend. Kidney tissues were fixed in4%paraformaldehyde andembedded in paraffin for light microscopy and immunohistochemistry. Theparaformaldehyde-fixed and paraffin-embedded kidney tissues were cut intosections of4μm thick for stained with matoxylin-eosin (HE), periodicacid-schiff (PAS), immunohistochemistry and TUNEL staining. HE and PASstaining were used to observe the pathological changes.Immunohistochemistry was used to analyze the renal expression of Shh, Ptch1,Smo and Gli2. BG, serum creatinine (Scr), serum total cholesterol (TC),triglyceride (TG), urine protein (Ucr), and hypertrophy index (the ratio ofkidney weight: body weight) were evaluated in every group. The apoptosis ofrenal tubular epithelial cells were stained by TUNEL. The protein level of Shh,Ptch1, Smo, Gli2, P53, Bax, cleaved caspase-3were detected by western blotand the level of mRNA for Shh and Gli2were detected by real time PCR. Allthe data were analysed by SPSS15.0statistics software, P value＜0.05wasconsidered to have statistical significance.
Result:
Part1: Compare to normal tissue, the expression of shh, Ptch1, Smo andGli2decreased and apoptosis increased in diabetic nephropathy. There was asignificant difference between normal and diabetic nephropathy group (p＜0.05).
Part2: In vitro, the apoptosis of HK-2cells reached a peak in48hoursafter incubated with high glucose compare to12h,24h and72h (p＜0.05).Western blot analyzed the expression of protein level found that Shh, Ptch1,Smo, Gli2were declined and p53、Bax、cleaved caspase3were rised when high glucose induced for48h (p＜0.05) as well as mRNA of Shh and Gli2alsoincreased (p＜0.05).
After cells were transfected with Shh siRNA, the percentage of apoptosisin HK-2cells was higher than non-transfection group, and the levels of Shh,Ptch1, Smo, Gli2protein were higher, which have statistical significance whencompared with HG group.The expression of p53, Bax and cleaved caspase3were higher in transfection group than non-transfecting (p＜0.05).
Stimulated HK-2cells with recombinant human Shh protein, theapoptosis rate decreased, and p53, Bax and cleaved caspase3expression wassignificantly lower than HG group (p＜0.05). But the protein levels of Shh,Ptch1, Smo, Gli2and mRNA level of Gli2were significantly up-regulated (p＜0.05).
When stimulated HK-2cells with resveratrol, result in the apoptosis rateand p53, Bax and cleaved caspase3expression were lower than HG group (p＜0.05), and the protein levels of Shh, Ptch1, Smo, Gli2and mRNA levels ofShh, Gli2were significantly up-regulated (p＜0.05).
Part3: Polydipsia, polyphagia and polyuria of diabetic symptoms wereappeared after the mice were injected with STZ for about3days. There were asmall amount of lymphoid mononuclear cell infiltration in tubulointerstitialafter injected STZ for8weeks, and it was found that a large amount oflymphoid mononuclear cell infiltration in the tubules, tubular epithelial cellsof the fluff off, tubular dilatation when STZ injected for12weeks and24weeks. However, there were no significantly lesions in glomerular mesangialcompared to control group and model group.
At week-12, Scr and KW/BW ratio are the lowest in the control group,the highest in the model group, followed by treatment group, there aresignificant differences among the three groups (p＜0.05). Compared withmodel group, the levels of Shh, Ptch1, Smo and Gli2and mRNA of Shh andGli2were upregualted and p53, Bax and cleaved caspase3weredownregulated in treatment group (p＜0.05). The apoptosis of renal tubularepithelial cells in treatment group was higher than control group, but lower than model group (p＜0.05).
Conclusions:
1There was basic expression of Shh signaling pathway in normal humanrenal tissues, but Shh signaling pathway was inhibited in renal tubularepithelial cells of diabete.
2In HK-2, interfered Shh gene expression by siRNA, which can inducethe activation of caspase3and increase the expression of p53and Bax, andpromote apoptosis. It is suggested that Shh signaling pathway might involvedin the apoptosis of HK-2cells, which reduced by high glucose.
3The expression of p53, Bax and caspase3were decreased when addedrecombinant human Shh protein to activate Shh pathway in HK-2, it is showedthat Shh can inhibit apoptosis of tubular cells which were stimulated with highglucose. Which provide a new idea for prevention and treatment of diabeticnephropathy.
4The date shown that resveratrol can adjusted Shh, Ptch1, Smo and Gli2expression by gene and protein levels, and then regulated p53, Bax andcaspase3expression, thereby inhibiting high glucose-induced apoptosis ofrenal tubular epithelial cells. Therefore, resveratrol may be a novel materialfor the prevention and treatment of diabetic nephropathy.
引文
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