慢性肾衰中甲状旁腺激素／甲状旁腺激素相关蛋白的研究进展

当慢性肾衰患者肾小球滤过率下降到 50ｍｌ/ｍｉｎ时 ,在低钙血症、高磷血症、活性维生素Ｄ缺乏及钙受体、维生素Ｄ受体下调等因素独立或共同的作用下 ,血清甲状旁腺激素 (ＰＴＨ)水平显著增高 ,其升高程度与病情进展相一致。同时 ,与ＰＴＨ高度同源的甲状旁腺激素相关蛋白 (ＰＴＨｒＰ)血清水平也出现升高 ,其同样与ＰＴＨ/ＰＴＨｒＰ受体结合 ,产生相同效应。过度增高的血清ＰＴＨ/ＰＴＨｒＰ不仅影响骨质代谢 ,而且对心血管系统、免疫系统、肾脏和内分泌组织均有负性影响 ,并已经成为一种新型的尿毒症毒素 ,作为诊断肾衰进展的重要指标 ,…     

慢性肾功能衰竭继发性甲旁亢大鼠甲状旁腺钙敏感受体改变

继发性甲状旁腺功能亢进 (ｓｅｃｏｎｄａｒｙｈｙｐｅｒ ｐａｒａｔｈｙｒｏｉｄｉｓｍ ,ＳＨＰＴ)是慢性肾功能衰竭 (ＣＲＦ)的常见并发症。近年来随着钙敏感受体的克隆[1] ,普遍认为细胞外钙离子通过与甲状旁腺钙敏感受体(ｐａｒａｔｈｙｒｏｉｄｃａｌｃｉｕｍｓｅｎｓｉｎｇｒｅｃｅｐｔｏｒ ,ＰＣａＲ)结合 ,调节甲状旁腺素 (ＰＴＨ)分泌 ,并有可能调节甲状旁腺增生。但ＰＣａＲ的ｍＲＮＡ水平在ＳＨＰＴ发病中是否有变化 ,对此报道不一[2 ,3] 。 1,2 5(ＯＨ) 2 Ｄ3作为治疗ＳＨＰＴ的重要手段 ,是否对ＰＣａＲｍＲＮＡ水平有影响 ?本…     

慢性肾衰竭继发性甲状旁腺功能亢进患者的甲状旁腺钙受体mRNA的表达

已证实胞外Ｃａ2 + 可通过激活甲状旁腺主细胞的钙敏感受体 (ＣａＲ)来调节甲状旁腺激素 (ＰＴＨ)的释放[1 ] 。在继发性甲状旁腺功能亢进 (ＳＨＰＴ)患者 ,血ＰＴＨ常明显增高 ,与血Ｃａ2 + 变化不平行。本研究旨在探讨ＣａＲ是否在ＳＨＰＴ的发病过程中起重要作用。一、材料与方法1 .组织来源 :(1 )ＳＨＰＴ组 :取自因严重ＳＨＰＴ行甲状旁腺全切加前臂移植术的尿毒症患者 ,其中弥漫性增生 (ＤＨ)及结节性增生 (ＮＨ)组织各 5枚。 (2 )正常对照组 :取自新鲜的供肾尸体 ,男 3例 ,女 2例 ,平均年龄 (33 46± 2 1 8)岁 ,血清ｉＰＴＨ为 (32 …     

慢性肾衰患者甲状旁腺激素与左心室结构和功能的关系

目的：心血管并发症是慢性肾衰（CRF）一个常见而严重并发症。CRF患者常伴继发性甲旁亢（SHPT）,有甲状旁腺激素（PTH）的增高,为了解PTH的增高与左室结构与功能的关系特作此研究。方法：通过对60例维持性血透患者心超与心功能检测及与血PTH的相关分析,了解CRF患者心脏结构与功能改变特征及PTH的关系。结果：76．6％ CRF患者有左室肥厚（LVH）,其中52．2％为偏心性肥厚,43．5％为向心性肥厚,4．3％为单纯扩张,心功能损害以左心舒张功能受累为主,占81．7％,并出现早。54／60例（90％）血PTH增高,且与左室后壁厚度（LVPWT）,室间隔厚度（IVST）,左室心肌重量指数（LVMI）正相关,与左室舒张功能E／A负相关。结论：CRF时血PTH增高是影响左结构与功能的重要因素之一。     

慢性肾功能不全患者血清甲状旁腺激素水平的变化分析

目的分析慢性肾功能不全(CRF)患者血清甲状旁腺激素(PTH)水平的变化情况。方法选取2013-09~2014-12肾内科诊断为CRF住院患者306例。按我国CRF的分期方法,根据血清肌酐水平(Cre,单位μmol/L,肌氨酸氧化酶法)分为:肾功能不全代偿期25例(133.8Cre171.5);肾功能不全失代偿期85例(194.0Cre440.8);肾功能衰竭期79例(456.3Cre703.6);尿毒症期117例(802.4Cre2044.9),并以正常成人42名为对照组。用化学发光法对血清全段PTH水平进行检测,观察其在肾病不同阶段的变化情况。结果 CRF患者PTH水平高于正常对照组,随着病情进展PTH水平逐渐增高。结论监测血清PTH水平能客观地评价肾功能损害程度,对防治CRF具有重要的意义。     

慢性肾功能衰竭继发性甲状旁腺机能亢进症骨病

慢性肾功能衰竭继发性甲状旁腺机能亢进症骨病杜学海慢性肾功能衰竭（肾衰）可通过多种原因产生骨病，最重要者为继发性甲状旁腺机能亢进症（甲旁亢）骨病，其他为铝相关性骨病和β２－微球蛋白沉积引起的淀粉样变，可统称为肾性骨营养不良或肾性骨病。现仅就继发性甲旁亢...     

慢性肾功能衰竭患者血降钙素的变化

作者用放射免疫测定法观察了２９例慢性肾功能衰竭（ＣＲＦ）患者血降钙素（ＣＴ）的变化。结果表明，ＣＲＦ及血液透析（ＨＤ）、血液滤过（ＨＦ）患者血ＣＴ值均明显高于正常对照组（Ｐ＜０．０１）。ＣＲＦ患者水平升高与血Ｃｒ、ＢＵＮ、Ｃａ和Ｐ相关无显著性差异；经ＨＤ治疗后ＣＴ值无明显变化；ＨＦ治疗后ＣＴ值明显下降，但其下降率明显低于小分子物质ＢＵＮ、Ｃｒ。     

慢性肾功能衰竭患者维生素D受体基因多态性与肾性骨病的关系

目的 探讨慢性肾功能衰竭（CRF）患者维生素D受体（VDR）基因多态性与肾性骨病（RO）发病的关系。方法 用RFLPs法检测87例CRF患者VDR基因型,用超声骨密度检测法检测患者跟骨骨密度（骨超声振幅衰减BUA）,用放免法检测患者血全段甲状旁腺素（iPTH）。然后分析相应数据,考察VDR与BUA及甲状旁腺素的关系。结果 VDR基因型主要分布在Bb和bb两型（97.68%）。Bb与bb二型患者BUA均低于正常参考值,且三组数据比较差异有非常显著性（P＜0.01）。三型间血全段甲状旁腺素水平亦有差异（P＜0.01）。结论 VDR基因型对慢性肾衰患者骨代谢有决定性影响,为筛选患者中RO和继发甲状旁腺机能亢进症（SHPT）高发人群提供参考。     

甲状旁腺激素受体1在糖尿病合并乳腺浸润性导管癌患者的表达及意义

目的 观察甲状旁腺激素受体1 (PTH1R)在糖尿病合并乳腺浸润性导管癌组织中的表达及其临床意义.方法 应用免疫组织化学法检测32例糖尿病合并乳腺浸润性导管癌患者及71例非糖尿病合并乳腺浸润性导管癌患者组织PTH1R表达,并结合临床预后进行对比分析.结果 乳腺浸润性导管癌组织中,糖尿病患者PTH1R阳性表达率高于非糖尿病患者(P＜0.05).PTH1R表达水平随着糖尿病合并乳腺浸润性导管癌患者预后不良而升高.结论 糖尿病状态下PTH1 R表达水平与乳腺浸润性导管癌预后有关,抑制PTH1R表达可能为糖尿病合并乳腺癌治疗有效靶点之一.     

Changes in canine leukocyte glucocorticoid receptors during endotoxin shock

We studied changes in canine leukocyte glucocorticoid receptors during endotoxin shock. Blood samples for analysis were collected and leukocytes were isolated just prior to and 2 and 6 hours after endotoxin administration. Employing 3H-dexamethasone (3H-Dex) as a ligand, we studied 3H-Dex-specific binding of the leukocytes in dogs and their changes during endotoxin shock. Results from two groups (anesthetized and conscious) showed that the specific binding of the leukocytes decreased significantly 2 hours after endotoxin administration in both groups and 6 hours after endotoxin in anesthetized dogs. In conscious dogs, the specific binding returned to normal by 6 hours. No correlation was found between the changes of serum cortisol and 3H-Dex-specific binding. It may be suggested that perturbations in glucocorticoid hormone action at the receptor level might be involved in the pathogenesis of endotoxin shock.     

Genetics of glucocorticoid receptors

The lymphocytolytic effect of glucocorticoids has been used for isolating receptor mutants. They fall into several groups with defects either in the hormone binding domain or the DNA binding domain or with part of the receptor polypeptide missing. These truncated receptors have increased binding affinity for general DNA and are synthesized from 5'-truncated messages. In addition, a phenotype has been identified in which a receptor allele, although apparently normal, is shut-off with no gene product detectable. The wild-type receptor polypeptide of about 95,000 molecular weight is synthesized from two mRNAs of 7 kb and 5 kb which differ in the lengths of their 3'-untranslated regions. A receptor model with three linearly arranged and functionally distinct domains is discussed. The DNA binding domain is rich in basic amino acids and cysteines and is located in the middle of the polypeptide. This region has the highest degree of homology with the estrogen receptor and with the v-erb-A oncogene product.     

Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

Glucocorticoids (GCs) are commonly used to treat a variety of immune diseases. However, the efficacy of treatment is greatly influenced by an individual variation in sensitivity to GCs, which is caused by differences in the glucocorticoid receptor (GR). The variable receptor profile results from variations in the GR gene, or alternative splicing of the gene coded. We investigated the evolution of the GR gene by comparing genomic GR sequences of vertebrates. Exon length and amino acid sequence are conserved among all classes of vertebrates studied, which indicates strong evolutionary pressure on conservation of this gene. Interestingly, teleostean fishes have two different GR proteins. One of the duplicate fish GR genes has a nine-amino-acid insert in the DNA binding region that results from alternative splicing. The duplicate GR genes and products of alternative splicing in teleostean fishes are differentially expressed in vivo and show different transactivation capacity in vitro. The presence of two GR genes appears to be a result of divergence of receptors rather than of ligands. Teleostean fishes express different, evolutionarily related, functional GR proteins within a single organism. Hereby, teleostean fishes present a model that facilitates investigation of the molecular basis of cortisol resistance and different regulatory functions of cortisol.     

The effects of glucocorticoid therapy on glucocorticoid receptors in leukemia and lymphoma

Measurement of glucocorticoid receptors appears to be useful for selecting which patients with leukemia and lymphoma should receive glucocorticoid therapy. To determine the effect of recent or concurrent glucocorticoid therapy on the number of measured tumor glucocorticoid receptor sites, 18 patients with leukemia and lymphoma were studied. Baseline determinations of numbers of glucocorticoid receptors were performed on the malignant cells circulating in the patients' peripheral blood. Glucocorticoid therapy was then instituted consisting of dexamethasone 4 mg p.o. every 6 hr. Repeat determinations of the number of glucocorticoid receptor sites were performed within 24 hr and at various subsequent times from the start of therapy. When compared to baseline receptor numbers, 16 of 18 patients demonstrated a decrease in receptor number (median decrease 1651 sites/cell) after the start of glucocorticoid therapy. The magnitude of the change in receptor number was independent on the initial number of receptors. Our results suggest that in order accurately interpret glucocorticoid receptor numbers in patients with leukemia and lymphoma, glucocorticoid should not be administered for 3 wk prior to determinations of receptor levels.     

Changes in net charge of glucocorticoid receptors by activation, and evidence for a biphasic activation kinetics

The kinetics of glucocorticoid receptor activation and the changes in molecular properties of the receptors by the activation were studied, employing aqueous two-phase partitioning of rat thymocyte, rat liver and mouse S49.1 lymphoma cell cytosol labelled with tritiated glucocorticoid. By a mathematical analysis of the time-course of the receptor partition coefficient during activation, we demonstrate that at least two different receptor conversions take place during this process. Partitionings at conditions excluding receptor aggregation allowed an evaluation of differences in net charge between activated and non-activated forms of native and chymotrypsin-treated receptors. The net charge of the chymotrypsinized receptor changes little by the activation, being between 0 and -10 at pH 8 both in the non-activated and the activated state. In contrast, the activation changes the net charge of the native receptor from around -50 to around -10.     

Modulation of DNA binding of glucocorticoid receptors

Glucocorticoid receptors of several rodent and human cell lines were subjected to mild proteolysis with several proteases. A hormone binding fragment of Mr approximately 40,000 was generated which had increased affinity for DNA as revealed by DNA-cellulose chromatography. It behaved similar to the truncated nti ('increased nuclear transfer') receptor of mutant mouse lymphoma cells. These data led to the view that wild-type receptors of Mr approximately 94,000 contain in addition to the functional domains for hormone binding and interaction with DNA a third domain ('modulation domain') which is essential for biological activity. Monoclonal antibodies against wild-type receptors were used in DNA binding experiments and increased affinity for DNA was observed. The data suggest that reacting the receptor with antibody leads to functional elimination of the modulation domain as if it were cleaved off by mild proteolysis. Antibody treatment neither caused nor inhibited receptor activation to a DNA binding form.     

Glucocorticoids and lymphocytes. III. Effects of glucocorticoid administration on lymphocyte glucocorticoid receptors

To determine the effects of glucocorticoid administration on the number of measured lymphocyte glucocorticoid receptor sites and the duration of such effects, seven normal volunteers were studied. Glucocorticoid receptor levels of the lymphocytes circulating in the blood of each volunteer were determined. Glucocorticoid was then administered in a regimen of a total of four doses of dexamethasone 4 mg p.o. every 6 hr. Determinations of the number of receptors were performed at 6 hr and at various subsequent times after the end of dexamethasone administration. When compared to baseline receptor numbers, six volunteers showed a decrease in receptor number after glucocorticoid administration (median maximum decrease 2,046 sites/cell). The fall in receptor number occurred rapidly, reaching a nadir within 30 hr from the end of glucocorticoid administration. The return of receptor number to baseline was more gradual, requiring from 3 to as long as 17 days in one subject. Our results suggest that in order to accurately interpret glucocorticoid receptor numbers in human lymphoid cells, glucocorticoid should not have been administered for 3 wk prior to determinations of receptor levels.