CaSR对糖尿病并发症型的调控作用研究进展
Research Progress in the Regulation of CaSR on Complications of Diabetes
DOI: 10.12677/ACM.2023.1371591, PDF, HTML, XML, 下载: 251  浏览: 336 
作者: 刘婧文：黑龙江中医药大学基础医学院，黑龙江 哈尔滨
关键词: 糖尿病并发症；钙敏感受体；糖尿病；研究进展；Complications of Diabetes； Calcium Sensitive Receptors； Diabetes； Research Progress
摘要: 糖尿病是一种代谢类疾病，近年来随着人们生活水平的逐渐增高，糖尿病患者人数日益增长，我国是全世界患二型糖尿病人数最多的国家。糖尿病会使许多器官受到损伤，包括心脏、肾脏、睾丸、脑部神经元以及周围神经等，进而导致糖尿病并发症的发生。钙敏感受体(CaSR)是一种C类G蛋白偶联受体，常与一些钙稳态类疾病相关，如原发性和继发性甲状旁腺功能亢进症、恶性肿瘤高钙血症、常染色体显性遗传性低钙血症等。本文主要整理了CaSR在糖尿病并发症中发挥的调控作用，为CaSR作为疾病治疗靶点提供新思路。
Abstract: Diabetes is a metabolic disease. In recent years, with the gradual increase of people’s living stand-ards, the number of patients with diabetes is growing. China has the largest number of type 2 dia-betes patients in the world. Diabetes can damage many organs, including the heart, kidney, testis, brain neurons and peripheral nerves, which will lead to complications of diabetes. Calcium sensitive receptor (CaSR) is a class C G protein-coupled receptor, which is often associated with some calcium homeostasis diseases, such as primary and secondary hyperparathyroidism, malignant tumor hy-percalcemia, autosomal dominant hereditary hypocalcemia, etc. This article mainly reviews the regulatory role of CaSR in the complications of diabetes, and provides new ideas for CaSR as a target for disease treatment.
文章引用：刘婧文. CaSR对糖尿病并发症型的调控作用研究进展[J]. 临床医学进展, 2023, 13(7): 11382-11386. https://doi.org/10.12677/ACM.2023.1371591

1. 糖尿病心血管疾病

CaSR可在心脏中表达。早有研究人员通过给予新生大鼠心肌细胞以CaSR激动剂GdCL3 (三氯化钆)来研究CaSR与心肌细胞凋亡的关系。结果发现激动CaSR可增加细胞外调节蛋白酶(ERK)、c-Jun NH(2)末端蛋白激酶(JNK)和p38的磷酸化和激活半胱天冬酶9，进而促进新生大鼠心肌细胞凋亡 [1] 。齐汉平等人同时给予了心肌细胞NPS-2390 (CaSR抑制剂)，他们的研究结果也证实了上述结论 [2] 。但同时也有研究发现，在糖尿病性心肌病(DCM)的发展中，心肌的CaSR (糖尿病四周大鼠与糖尿病八周大鼠与对照组相比分别呈现50%与75%的CaSR蛋白表达降低)。蛋白激酶Cα (PKC-α)和钙处理调节因子(如磷酸兰班(PLN)、Ca(2+)-ATP酶(SERCA)和Ryanodine受体(RyR))表达均降低，这似乎与上述结论相反 [3] 。

精胺是CaSR的直接激动剂(CaSR除了能和Ca2+结合外，其他阳离子和多胺类也能够使CaSR活化) [4] ，使用精胺可以延缓DCM中出现的心脏的异常结构和收缩和舒张功能障碍。王跃红等人发现，精胺可能通过抑制活性氧(ROS)释放，以及抑制Nrf2-ROS-p53-MuRF1信号通路使CaSR表达下降，达到精胺对糖尿病大鼠心脏的保护作用 [5] 。

CaSR还可引起磷酸肌醇的积累进而增加细胞内钙的释放，并且可以参与血管紧张素II (AngII)通过磷酸酶钙调磷酸酶(CaN)途径诱导的心脏肥大 [6] 。还有研究人员发现CaSR激活也可诱导心脏成纤维细胞(CFs)中的Ca2+浓度升高，Smurf2-泛素蛋白酶体和自噬 [7] ，并增强CFs的增殖，同时Col (胶原蛋白)的过度沉积，导致心肌纤维化 [8] 。

2. 糖尿病肾病

肾缺血再灌注损伤(RI/RI)时糖尿病常见的并发症之一，发生的同时会导致体内钙浓度失衡进而使炎症发生、脂代谢异常等情况。胡波等人研究发现，CaSR激活可导参与糖尿病RI/RI期间肾小管上皮细胞的损伤，导致脂质过氧化，炎症反应，亚硝基氧化还原失衡和细胞凋亡 [9] 。糖尿病肾病也会导致血管钙化的发生，陈筱涛等人研究发现在糖尿病肾病(DN)血管钙化的过程中，CaSR的表达降低导致了成骨基因的表达被促进进而诱导了钙的沉积，提示CaSR可能成为诊断DN患者发生血管钙化的标志物 [10] 。还有研究发现CaSR在原发性膜性肾病(PMN)中也起关键作用，抑制CaSR使细胞内钙水平升高，并且使核酸酶，蛋白酶活化，促进前列腺素，细胞因子和超氧自由基的释放，提示当钙信号传导被中断时可能导致PMN发展为终末期肾病(ESRD) [11] 。

3. 糖尿病脑病

糖尿病性脑病是糖尿病十分常见的并发症，有研究人员发现在糖尿病大鼠海马神经元中，CaSR可调节PLC-IP2途径Ca离子水平，当CaSR下调时可伴有神经元损伤，钙紊乱以及ROS增加并且NO释放减少，当CaSR表达上调时可减弱这些变化，提示CaSR的表达可减缓大鼠糖尿病性脑病的发生 [12] 。当使用钙通道阻滞剂尼莫地平的时候，可使细胞内游离Ca(2+)水平正常化，进而调节钙稳态，可能与调节糖尿病脑病认知缺陷相关 [13] 。

4. 其他糖尿病并发症

尤哲忠等人发现药物西那卡塞可通过增加糖尿病db/db小鼠CaSR的表达，以及坐骨神经中CaMKKβ-LKB-1-AMPK-eNOS (钙调蛋白依赖性蛋白激酶激酶β (CaMKKβ)，肝激酶B1 (LKB1)，内皮一氧化氮合酶(eNOS)，AMP活化蛋白激酶(AMPK))通路的激活来改善炎症，细胞凋亡和自噬，进而在糖尿病周围神经病变的治疗中发挥重要作用 [14] 。CaSR还可以调节内源性胱硫硫氨酸-γ-裂解酶/硫化氢(CSE/H2S)途径，进而抑制糖尿病模型大鼠中的血管平滑肌细胞(VSMC)增殖。在糖尿病肝损伤动物及细胞模型中，邵毅英等人发现模型组大鼠的CaSR表达升高同时伴随着肝纤维化指标(如胶原I (COI)、胶原III (COIII)，基质金属蛋白酶9 (MMP9)等)的上升，提示CaSR的激活可能为糖尿病肝损伤的原因之一 [15] 。

此外值得注意的是，在怀孕期间，胎儿血液中的矿物质浓度，特别是钙和磷的浓度保持在较高水平，以便发育中的骨骼可以增加足够的矿物质含量。在患有妊娠糖尿病(GDM)的胎盘中检测出CaSR的表达低于健康对照组，这可能导致出生后低钙血症的发生 [16] 。LCG (水蛭和蜈蚣颗粒)通过增加NO (一氧化氮)生成显着改善了DMED (糖尿病勃起功能障碍)大鼠的勃起功能，抑制内皮细胞凋亡和纤维化，这可能受益于DMED大鼠中CaSR/PLC/PKC通路的抑制 [17] 。

5. 讨论与展望

CaSR是G蛋白偶联受体，可通过与异源三聚体G蛋白(由α，β，γ三种亚型组成)结合发出信号，其中Gα蛋白有五类(Gs、Gi、Go、Gq/11、G12/13)，可参与体内多种关键的生理过程 [18] 。糖尿病是一种慢性代谢类疾病，其特征是血糖水平升高。如果长期使机体处在高血糖状态下，胰岛素的缺乏会对机体产生很多严重损伤，导致多种并发症的发生。糖尿病患者常合并脑部病变、神经病变，糖尿病足，心血管疾病，神经损伤，以及一些急性的并发症。其并发症严重影响了糖尿病患者的生活，有的甚至威胁到患者生命。本综述整理了国内外近些年对CaSR在糖尿病并发症中的作用。发现在心脏中给予GdCL3和精胺等GaSR激动剂可激活ERK、JNK、p38相关蛋白以及Nrf2-ROS-p53-MuRF1信号通路来促进心肌细胞凋亡，进而损伤心脏 [19] 。在糖尿病肾病组织中，CaSR表达也会诱导成骨基因表达导致钙的沉积，同时CaSR也会参与糖尿病肾病期间肾小管上皮细胞损伤，使一系列炎症、细胞凋亡发生。但在糖尿病脑病的发生发展中，研究人员发现CaSR的表达可减缓大鼠糖尿病性脑病的发生。此外，还有大量研究人员发现，激动GaSR可以调节糖尿病中的血糖水平及血脂情况。例如苦参碱可以通过激动CaSR刺激肠道内GLP-1的分泌达到调节血糖水平的作用 [20] [21] 。

目前有大量研究人员在探寻糖尿病及其相关并发症中的治疗靶点，本文从CaSR角度出发，探究其在不同组织中发挥的作用，为进一步研究糖尿病的治疗奠定基础 [22] 。

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