摘要
糖尿病(Diabetes mellitus, DM)的发病率在世界范围内呈快速增长的趋势。糖尿病视网膜病变(Diabetic retinopathy, DR)是糖尿病最为常见的严重并发症,是造成成年人失明的主要原因。DR的临床症状主要包括:视网膜血管渗透性增加、水肿以及内皮细胞增生等。目前,治疗DR最主要的方法是全视网膜光凝固法(Panretinal photocoagulation, PRP)。减少DR发病率的方法主要包括控制糖尿病患者血糖水平和血压。然而,一些患者尽管能很好的控制血糖水平和血压,但仍会发展成DR。因此寻找一种新的防治DR的方法已成为必需。长期以来,DR的防治重点是针对血管病变。然而,越来越多的研究发现,糖尿病患者眼底出现可测的微血管病变之前就出现了视网膜Müller细胞功能的改变,Müller细胞的改变先于血管改变,Müller细胞的改变最终导致视网膜微血管发生病变,并且随着微血管病变的出现,进一步发展。所以,从临床意义出发,对DR的防治重点应在视网膜血管病变之前。
一些研究报道,Müller细胞凋亡、胶质原纤维酸性蛋白(Glial fibrillary acidic protein, GFAP)在Müller细胞中过表达、Müller细胞中血管内皮细胞生长因子(vascular endothelial growth factor, VEGF)分泌增加和谷氨酸代谢异常可能是糖尿病引起视网膜功能损害的早期因素,这些因素继而引起视网膜内谷氨酸浓度增加,增加的谷氨酸浓度会过度刺激突触后神经元细胞膜上的谷氨酸受体,对神经细胞造成明显的毒性作用,并且谷氨酸浓度过高会加速视网膜微血管细胞的死亡,进而发展成临床可见的DR。近年来,对Müller细胞的研究主要集中在其转运和清除神经元释放的谷氨酸的能力上。谷氨酸转运体(Glutamate transporters, GLAST)、谷氨酰胺合成酶(Glutamine synthetase, GS)以及谷氨酸脱羧酶(Glutamate decarboxylase, GAD)是Müller细胞转运并降解谷氨酸的几个重要环节。Müller细胞通过其胞膜上的GLAST摄取神经元释放的谷氨酸,摄入的谷氨酸经Müller细胞内GS转化成无毒的谷氨酰胺,谷氨酰胺再运出细胞外提供给神经元合成谷氨酸。摄入Müller细胞的谷氨酸也可经细胞内的GAD降解成γ-氨基丁酸(γ-aminobutyric acid, GABA)。通过这种方式,视网膜神经递质池被重新补充,谷氨酸兴奋毒性受到抑制。
牛磺酸是视网膜组织中含量较高的一种游离氨基酸。以往研究表明,牛磺酸在视网膜中具有多种复杂的生物学效应。与视网膜神经组织的发育、分化、正常结构及功能的维持、移植后的再生及一些视网膜疾病的发病机制都有密切的联系。视网膜是通过血-视网膜屏障来富集牛磺酸的,牛磺酸脂溶性差,通过细胞膜的速度较慢,但其在视网膜细胞内外的浓度差可达400:1,这是由于视网膜细胞上存在大量牛磺酸转运蛋白(Taurine transporter,TauT),所以牛磺酸能很快进入视网膜细胞,发挥其视觉保护作用。有实验证实,在高血糖患者体内,大量山梨醇聚集可引起体内代偿性的牛磺酸消耗增加,从而使视网膜色素上皮细胞、血小板、神经以及晶状体中牛磺酸含量降低。已经证实,糖尿病时细胞内牛磺酸缺乏是引起慢性细胞毒性的一个主要因素。临床研究发现,给胰岛素依赖型糖尿病病人膳食中补充牛磺酸,可使血浆和血小板中牛磺酸水平恢复正常,血小板聚集得到改善。另外,牛磺酸还可以降低糖尿病死亡率。尽管牛磺酸对糖尿病的防护效应已经得到证实,牛磺酸对糖尿病诱导的Müller细胞改变的防护作用没有报道。
基于以上分析,我们推测,牛磺酸可能对糖尿病引起视网膜Müller细胞改变具有防护效应。本研究体内实验采用链脲佐菌素(streptozotocin, STZ)诱导的Sprague-Dawley (SD)大鼠糖尿病模型,以牛磺酸强化的饲料对糖尿病大鼠进行营养干预。体外实验采用SD大鼠视网膜Müller细胞高糖模型,在培养介质中添加牛磺酸干预。通过HE染色、电镜、TUNEL、ERG、免疫组织化学、氨基酸分析、免疫细胞化学、激光共聚焦分析技术、流式细胞技术、RT-PCR、Western blotting、放射液闪等先进实验技术方法,在体内观察糖尿病诱导的大鼠视网膜结构和功能的改变及牛磺酸的防护效应,体外观察高糖诱导的Müller细胞形态和功能的改变及牛磺酸的防护效应,并在体内外进一步研究牛磺酸防护糖尿病和高糖引起的Müller细胞改变的分子机制。
主要结果和结论如下:
1. STZ诱导糖尿病12周后,大鼠视网膜内核层(Inner nuclear layer, INL)和神经节细胞层(Ganglion cell layer, GCL)细胞数显著减少,Müller细胞胞体出现肿胀。超微结构显示,Müller细胞核固缩,核电子密度增大,染色质边集,细胞空泡变性。5%牛磺酸干预后,以上病理改变和超微损伤明显减轻。但牛磺酸干预对血糖没有明显影响,提示牛磺酸对糖尿病大鼠早期视网膜病变的防护作用并非通过降低血糖来实现的。
2.视网膜电图(Electroretinogram, ERG)检测结果显示,STZ诱导糖尿病8周后,大鼠视杆细胞反应a波、b波、最大反应b波、phot-ERG b波、OPs p4波的潜伏期明显延长,OPs Os1波的振幅明显降低。1%牛磺酸干预对以上各波的潜伏期无明显影响,但可增加OPs Os1波的振幅;5%牛磺酸干预可明显缩短视杆细胞反应a波、b波、最大反应b波、phot-ERG b波、OPs p4波的潜伏期,增加OPs Os1波的振幅。表明糖尿病早期即发生了视网膜神经功能损伤,牛磺酸对这一损伤具有明显的防护效应。
3. STZ诱导糖尿病2周时,视网膜中即可见少量TUNEL阳性细胞。12周时,视网膜中可见大量TUNEL阳性细胞,阳性细胞占总细胞的33%左右,主要分布在外核层和内核层。1%和5%牛磺酸干预均使视网膜中TUNEL阳性细胞数明显减少。Müller细胞经25 mmol/L高糖培养后,细胞形态发生明显改变,存活率明显降低,细胞核中出现典型的凋亡小体。流式细胞分析结果表明,高糖培养使Müller细胞凋亡率明显增加(高糖组36.52% vs正常对照组0.34%)。在培养介质中加入0.1mmol/L、1mmol/L和10mmol/L牛磺酸可显著提高Müller细胞存活率,降低Müller细胞凋亡率(低、中、高剂量牛磺酸组Müller细胞凋亡率分别是:16.43%、3.75%和2.01%)。
4. GFAP是胶质细胞反应性增生的标志物,VEGF是一种促新生血管形成的生长因子。体内STZ诱导糖尿病2、4、8和12周,大鼠视网膜GFAP、VEGF mRNA及蛋白水平呈时间依赖性上调。牛磺酸干预可有效拮抗GFAP、VEGF mRNA及蛋白表达上调。体外25 mmol/L高糖培养也使Müller细胞GFAP、VEGF mRNA及蛋白表达增加。1 mmol/L和10 mmol/L牛磺酸可有效抑制高糖诱导的GFAP、VEGF上调表达。体内外实验结果表明,牛磺酸可有效抑制糖尿病和高糖诱导的胶质细胞反应性增生、下调Müller细胞中VEGF的表达。
5.糖尿病和高糖诱导Müller细胞中TauT表达抑制,引起TauT mRNA及蛋白表达明显下降。牛磺酸干预可上调Müller细胞中TauT的表达,提高细胞内外牛磺酸的转运能力,从而有效抑制糖尿病引起的视网膜中牛磺酸浓度降低。
6. STZ诱导糖尿病引起视网膜内谷氨酸浓度显著升高。GLAST、GS和GAD是Müller细胞转运并降解谷氨酸的几个重要环节。糖尿病和高糖引起Müller细胞GLAST、GS和GAD mRNA及蛋白表达显著下降。高糖培养时,Müller细胞对L-[2,3-3H]-谷氨酸的摄取能力明显减弱。牛磺酸干预明显增加Müller细胞中GLAST、GS和GAD的表达,增强Müller细胞谷氨酸摄取能力,使视网膜中谷氨酸浓度明显降低,进而有效抑制糖尿病引起的谷氨酸兴奋毒性。
综上所述,糖尿病和高糖诱导Müller细胞结构和功能发生异常改变,牛磺酸对上述异常改变具有防护效应。进一步研究发现。牛磺酸通过提高Müller细胞牛磺酸转运能力、谷氨酸转运及清除能力来维持视网膜牛磺酸浓度的稳态及内环境的稳定。该实验结果为牛磺酸用于糖尿病早期视网膜病变的防治提供重要的实验依据。
Diabetes mellitus is increasing worldwide at an alarming rate. Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of legal blindness in working-age adults. The clinical hallmarks of DR include increased vascular permeability, leading to edema, and endothelial cell proliferation. The mainstay of therapy for DR is panretinal photocoagulation. Other agents that are known to decrease the risk of developing DR include controlling blood glucose levels and blood pressure, however, some patients develop retinopathy despite good control of blood glucose and blood pressure. Thus new therapies able to prevent the development or progression of DR are needed. Much of the research effort has been focused on vascular changes, but it is becoming apparent that other degenerative changes occur beyond the vascular cells of the retina. These include the altered expression of glial fibrillary acidic protein (GFAP) and vascular endothelial growth factor (VEGF) in the Müller cells, and always combined with alteration in glutamate metabolism.
Müller cells, the main glial cell within the retina, are vital for maintaining the normal health of the retina and have been implicated in many retinal diseases, including DR. Recently, some studies have demonstrated that the increased Müller cells’reactivity and Müller cells’glutamate dysmetabolism are early pathogenic events, which always resulted in an increment in retinal glutamate levels in diabetes. Increased glutamate can accelerate the death of retinal vascular cells and nonvascular cells, which might play an important role in the pathogenesis of retinopathy. A major physiological function of Müller cells is to regulate the ionic and molecular composition of the retinal microenvironment. An intensively investigated function of Müller cells was assumed as their ability to eliminate synaptically released glutamate, a neurotransmitter with more than 90% of the synapses placed in the retina. Glutamate transporters (GLAST), glutamine synthetase (GS) and glutamate decarboxylase (GAD) were found in Müller cells. So, it was postulated that synaptically released glutamate in retina was absorbed by Müller cells via GLAST transportation and rapidly converted to glutamine andγ-aminobutyric acid (GABA) with the aid of GS and GAD. The resulting glutamine was then returned to the neurons for glutamate re-synthesis. By this way, the neurotransmitter pool was replenished and glutamate neurotoxicity has been successfully prevented.
Taurine (2-aminoethanesulfonic acid), a sulphur-containingβ-amino acid, is one of the most abundant free amino acids in various tissues, and has been proved to play important roles in numerous physiological functions, such as osmoregulation, modulation of neurotransmitters, membrance stabilization, and antioxidation in mammals. It was concluded that intracellular depletion of taurine contributes much to chronic cytotoxicity in diabetes. Several studies have recently indicated that taurine exhibited beneficial effects in adults with DM. A lower level of taurine was clinically obtained in insulin-dependent and insulin-independent DM patients, taurine was decreased in plasma and platelets. In addition, an inverse correlation between the log of plasma taurine and glycosylated hemoglobin has been found. Moreover, in insulin-dependent diabetic patients, taurine supplementation decreased platelet aggregability, restored its own plasma and platelet levels, and abolished the inverse correlation between log plasma taurine and glycosylated hemoglobin. Moreover, the long-term dietary taurine supplementation retarded the morbidity of diabetes.
Based on the analysis above, we presume taurine maybe an effective protective agent of Müller cells changes induced by diabetes. The aim of this study was to investigate the effects of taurine supplementation on diabetes-induced Müller cells alterations in rats retina and the associated molecular mechanism. The Sprague-Dawley (SD) rats model of streptozotocin (STZ)-induced diabetes was used in vivo study. In vitro study, Müller cells cultured in high glucose were used as the model. TUNEL, immunohistochemistry, immuocytochemistry, amino acid analysis, laser confocal analytical assay, flow cytometry, RT-PCR and western blotting method were used to study the structural and functional changes induced by diabetes and high glucose. Meanwhile the proective effects of taurine and the associated molecular mechanism of taurine transporter, glutmate clearance pathway were deeply studied.
The main results and conclusions were summarized as follows:
1. The inner layer cells arranged irregularly and the intercellular spaces became wide in diabetic rats retina. The cells’number in inner nuclear layer (INL) and ganglion cell layer (GCL) was decreased obviously. Increased electron density, chromatin margination and karyopycnosis/karyorrhexis were observed easily in retinal Müller cells of diabetic rats. Some vacuolation appeared in the cytoplasm of Müller cells. Taurine treatment could significantly improve the changes of histopathology and ultrastructure in diabetic rats retina. Although no significant change has been observed with blood glucose content in taurine treatment group, taurine could protect the structural damages of retina induced by diabetes effectively, which indicating that the protective mechanisms of taurine was not by decreasing the levels of blood glucose in diabetic rats.
2. The implicit times of a and b wave of rod-response, b wave of max-response, p4 wave of OPs and b wave of phot-ERG of diabetic rats were respectively prolonged significantly compared to those of control ones. The Os1 amplitude of OPs was significantly decreased in diabetic rats. Although no significant improvement in 1% taurine treatment group, 5% taurine treatment could significantly reverse the changes of above wave, which suggesed that the functions of Müller cells changed in the early stage of diabetic rats and could be protected by taurine treatment.
3. In vivo study, some TUNEL-positive cells were observed in diabetic rats retina at 2 weeks. In 12 weeks, there were more TUNEL-positive cells found in diabetic rats retina than that in normal controls and the TUNEL-positive cells were 33% in total cells. When treatment with taurine, the TUNEL-positive percent was markedly decreased. In vitro study, increased karyopycnosis/karyorrhexis and some apoptotic bodies were found in high glucose cultured Müller cells. rate of apoptosis in Müller cells incubated in high glucose increased significantly (36.52% vs 0.34% in controls). Treatment with taurine could inhibit apoptosis (the apoptosis rate was 16.43%, 3.75% and 2.01% in low-dost, meta-dose and high-dose taurine group respectively).
4. A common marker for reactive gliosis is the well-described increase in the expression of GFAP. VEGF is a potent angiogenic growth factor. RT-PCR and western-blotting analysis showed increases in GFAP, VEGF mRNA and protein expression in STZ-induced diabetic retina and high glucose cultured Müller cells compared to normal controls. Treatment with taurine significantly blocked the increases in GFAP, VEGF mRNA and protein expression in diabetic retina and high glucose cultured Müller cells.
5. The level of taurine was decreased in untreated diabetic rats and was repleted by taurine supplementation. Our study suggested that the expression of TauT was reduced in diabetes and high glucose group and could be stimulated expression by taurine supplementation.
6. The concentration of glutamate was increased in untreated diabetic rats vs nondiabetic controls, and this increase was prevented by taurine. the expressions of GLAST, GS and GAD were reduced in diabetes and high glucose group and could be stimulated expression by taurine supplementation. The ability of L-[2,3-3H]-glutamate uptake was attenuated in Müller cells in high glutamate cultured group and could be potentized by taurine.
In brief, Our studies revealed that taurine ameliorates diabetic retinopathy possibly via increasing the ability of taurine transporter and relieving anti-excitotoxicity of glutamate, which suggest a possible utility of taurine as an adjuvant therapeutic agent in the management of diabetes and its complications.
引文
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