水通道蛋白在脓毒症中的作用

脓毒症是世界范围内重症监护病房常见的死亡原因.由于这种免疫综合征的复杂性,迫切需要开发新的治疗策略.水通道蛋白(aquaporins,AQPs)参与脓毒症的多种生理功能,其表达受到不同程度的调控.药物靶点或生物标记物可能存在水通道蛋白(AQPs)上,因为它们是调节脓毒症的关键.对水通道蛋白调节机制的进一步研究可能确定潜...     

肾上腺皮质激素对水通道蛋白表达的调节

肾上腺皮质激素参与水盐代谢的调节,盐皮质激素和糖皮质激素调节上皮细胞水通道蛋白 (Aquaporins,AQPs)的表达。盐皮质激素可使肾脏AQP3表达上调,对肾脏的AQP2表达依据刺激的时间不 同而表达不同,但对AQP1没有影响。糖皮质激素对不同组织器官AQPs的影响不尽相同。肾上腺皮质激素 对AQPs的调节作用在某些水代谢紊乱疾病的诊断与治疗方面可能有着广阔的应用前景。     

水通道基因表达和功能的调节

水通道,又称水蛋白(aquaporin,AQP),是一系列具有同源性的内在膜蛋白家族成员。它们介寻着不同类型细胞膜的跨膜水转运。迄今,已从哺乳动物组织中鉴定出6种水蛋白,除定位于肾集合管上皮细胞的AQP—CD特异地对加压素敏感外,限水和盐适应及某些药物也可影响AQPs的功能和表达。     

水通道蛋白调节剂对脑部疾病潜在的治疗价值

水通道蛋白(Aquaporins,AQPs)是一种膜蛋白,主要介导水分高效特异的跨膜转运.中枢神经系统主要表达AQP1、AQP4,参与控制脑组织水分的平衡,细胞的迁移和神经元的兴奋性.AQP4调节剂可作为脑卒中、外伤、肿瘤、感染、脑积水和癫痫新的治疗策略.在此我们就水通道蛋白在中枢神经系统的表达、作用及疾病研究中的新进展作一综述.     

胎儿发育中水通道蛋白的免疫组化观察

目的观察胎儿器官和组织发育过程中水通道蛋白(AQPs)的表达特征,初步探讨AQPs对胎儿发育进程的生物意义。方法14～38周胎儿共12例,取用肾脏、肺脏、唾液腺、甲状腺和胃等器官,常规固定、石蜡包埋和切片;用免疫组化S-P法,检测AQPs(AQP1、AQP2和AQP4)在胎儿不同胎龄器官组织中的表达。结果胎儿肾脏中AQPs定位于近端小管和集合管系统;胎肺中AQPs的表达随肺泡发育分化而迁移,始终定位于肺泡上皮;晚期胎肺中AQPs于肺泡及呼吸道上皮均有表达;胎16周起检出AQPs反应于唾液腺、胃腺和胰腺等消化腺,同时甲状腺中AQPs在滤泡上皮也有活跃表达。结论胎肾中AQPs的表达与肾的重吸收功能直接相关;胎肺内AQPs的表达反映肺泡上皮分化的轨迹,其调节水分的作用为肺泡发育提供空间;AQPs介导细胞内外水分的转运不但调节消化腺的分泌还参与调节甲状腺滤泡的激素合成和分泌过程。表明AQPs在胎儿发育过程,对各器官中水转运功能的成熟起重要作用。     

地塞米松对水通道蛋白1、4、5在大鼠变应性鼻炎鼻黏膜中表达的影响及意义

目的:确定水通道蛋白(AQPs)在大鼠变应性鼻炎时鼻黏膜上的表达及分布,并观察地塞米松对AQPs表达的影响,探讨AQPs与变应性鼻炎时水液分泌的关系.方法:健康SD大鼠随机分成空白组、假处理组、模型组、干预组,组织化学方法观察各组组织形态学特征,免疫组织化学方法(SP法)检测各组AQPs的表达并进行比较.结果:AQP1在血管内皮细胞、成纤维细胞中表达较强;AQP4表达于上皮细胞和上皮内腺上皮细胞及部分上皮下的腺上皮细胞;AQP5在上皮下部分腺上皮细胞成簇表达.经地塞米松处理后,AQP1、4、5的表达均有明显变化,仅AQP4在干预组间的表达并无明显改变.结论:AQP1、4、5在大鼠鼻黏膜上有不重叠表达;地塞米松能调节AQPs在鼻黏膜上的表达.     

水通道在冷冻保存中的应用研究进展

水通道(aquaporins,AQPs)是一类参与水快速转运的跨膜蛋白家族,广泛分布于动物、植物及微生物的生物膜表面,精细参与调节细胞跨膜的渗透平衡。近年来,AQPs在细胞转运水和冷冻保护剂中的作用倍受关注,AQPs能提高某些细胞和组织的冻融存活率,在低温保存中具有一定的应用前景。     

水通道蛋白与肿瘤血管新生

肿瘤血管新生对于肿瘤的生长具有重要作用。水通道蛋白在肿瘤组织中常出现表达异常，并且可以促进肿瘤血管的新生及包括肿瘤血管内皮在内的多种细胞的迁移，与此同时，水通道蛋白与肿瘤血管的高通透性有关，这可能是肿瘤组织对水通道蛋白缺失具有较高敏感性的原因。鉴于水通道蛋白对于肿瘤特别是肿瘤血管新生的影响，其抑制剂可能成为新的肿瘤治疗的目标靶点。     

水通道蛋白在急性实验染毒大鼠肾脏的表达及意义

目的观察水通道蛋白(AQPs)在正己烷急性染毒SD大鼠肾脏中的变化,结合观察损伤相关细胞因子TNF-α与EGFR的表达特征,初步探讨AQPs在实验染毒大鼠肾脏中的表达及其对自身修复的意义。方法建立SD大鼠正己烷急性染毒模型,取各组SD大鼠的肾脏,用4%多聚甲醛固定,常规石蜡包埋,切片厚度5μm,供HE染色和免疫组化。用免疫组化S-P法,检测AQPs(AQP1、AQP2和AQP4)以及损伤相关细胞因子TNF-α和EGFR在各组SD大鼠肾脏中的表达。结果①各组SD大鼠肾脏微细结构均达到受损要求。②免疫组化检测:AQP1反应位于肾脏近端小管上皮,尤其在顶质膜上呈明显增强;AQP2在集合管上皮表达也呈增强态势;AQP4在集合管基侧膜上却表达逐渐减弱。EGFR在肾脏集合管和远端小管上皮的表达,呈增强态势;TNF-α在集合管和远端小管表达也增强。结论正己烷染毒致SD大鼠肾脏结构明显受损,肾脏中AQPs的免疫组化表达也有明显的改变;正己烷中毒致肾脏中AQPs改变,对肾的尿液浓缩功能造成影响,甚至导致肾功能衰竭;肾脏损伤后,AQPs通过与相关活性因子TNF-α和EGFR等的协调作用,参与自身的修复与再生过程。     

肾脏水通道蛋白的研究进展

细胞内外水平衡是维持生命的关键因素之一。在发现水通道蛋白(Aquaporins，AQPs)以前，生理学家一直认为水是通过膜脂质双层结构进行简单扩散，但在某些组织细胞如红细胞、肾近曲小管细胞对水通透性甚高，不能用简单扩散来解释，于是推测此类细胞膜上可能存在某种功能性转运水的通道。1988年     

Aquaporins—new players in cancer biology

The aquaporins (AQPs) are small, integral-membrane proteins that selectively transport water across cell plasma membranes. A subset of AQPs, the aquaglyceroporins, also transport glycerol. AQPs are strongly expressed in tumor cells of different origins, particularly aggressive tumors. Recent discoveries of AQP involvement in cell migration and proliferation suggest that AQPs play key roles in tumor biology. AQP1 is ubiquitously expressed in tumor vascular endothelium, and AQP1-null mice show defective tumor angiogenesis resulting from impaired endothelial cell migration. AQP-expressing cancer cells show enhanced migration in vitro and greater local tumor invasion, tumor cell extravasation, and metastases in vivo. AQP-dependent cell migration may involve AQP-facilitated water influx into lamellipodia at the front edge of migrating cells. The aquaglyceroporin AQP3, which is found in normal epidermis and becomes upregulated in basal cell carcinoma, facilitates cell proliferation in different cell types. Remarkably, AQP3-null mice are resistant to skin tumorigenesis by a mechanism that may involve reduced tumor cell glycerol metabolism and ATP generation. Together, the data suggest that AQP expression in tumor cells and tumor vessels facilitates tumor growth and spread, suggesting AQP inhibition as a novel antitumor therapy.     

Aquaporins and cell migration

Aquaporin (AQP) water channels are expressed primarily in cell plasma membranes. In this paper, we review recent evidence that AQPs facilitate cell migration. AQP-dependent cell migration has been found in a variety of cell types in vitro and in mice in vivo. AQP1 deletion reduces endothelial cell migration, limiting tumor angiogenesis and growth. AQP4 deletion slows the migration of reactive astrocytes, impairing glial scarring after brain stab injury. AQP1-expressing tumor cells have enhanced metastatic potential and local infiltration. Impaired cell migration has also been seen in AQP1-deficient proximal tubule epithelial cells, and AQP3-deficient corneal epithelial cells, enterocytes, and skin keratinocytes. The mechanisms by which AQPs enhance cell migration are under investigation. We propose that, as a consequence of actin polymerization/depolymerization and transmembrane ionic fluxes, the cytoplasm adjacent to the leading edge of migrating cells undergoes rapid changes in osmolality. AQPs could thus facilitate osmotic water flow across the plasma membrane in cell protrusions that form during migration. AQP-dependent cell migration has potentially broad implications in angiogenesis, tumor metastasis, wound healing, glial scarring, and other events requiring rapid, directed cell movement. AQP inhibitors may thus have therapeutic potential in modulating these events, such as slowing tumor growth and spread, and reducing glial scarring after injury to allow neuronal regeneration.     

Intracellular aquaporins: clues for intracellular water transport?

Aquaporins (AQPs) are usually present at the plasma membrane to regulate influx and outflow of water and small molecules. They are important for the regulation of water homeostasis for the cells and organisms. AQPs are also present inside the cell, at the membranes of intracellular organelles. The roles of such AQPs have not yet been established. They will be clues to clarify the mechanisms of water and small solutes movements inside the cell. Recently, a new AQP subfamily has been identified with highly deviated asparagine-proline-alanine boxes, signature sequences for AQP. With limited homology less than 20%, this subfamily will be a superfamily of AQPs. Accordingly, it was tentatively named "superaquaporin subfamily," which is so far only present in multicellular organisms including plants, insects, nematodes, and vertebrates. Some superaquaporins are functionally water channels and localized intracellularly. AQP11, one of the two superaquaporins in mammals, has been shown to be important for the development of the proximal tubule as its disruption produced neonatally fatal polycystic kidneys in mice. Hence, recent identification of intracellular AQPs will open new areas of research on cell biology and expand the scope of AQPs.     

Aquaporins: Unexpected actors in autoimmune diseases

Aquaporins (AQPs), transmembrane proteins allowing the passage of water and sometimes other small solutes and molecules, are involved in autoimmune diseases including neuromyelitis optica, Sjögren's syndrome and rheumatoid arthritis. Both autoantibodies against AQPs and altered expression and/or trafficking of AQPs in various tissue cell types as well as inflammatory cells are playing key roles in pathogenesis of autoimmune diseases. Detection of autoantibodies against AQP4 in the central nervous system has paved the way for a deeper understanding in disease pathophysiology as well as enabling diagnosis. This review provides a comprehensive summary of the roles of AQPs in autoimmune diseases.     

Role of aquaporins in lung liquid physiology

Aquaporins (AQPs) are small, integral membrane proteins that facilitate water transport across cell membranes in response to osmotic gradients. Water transport across epithelia and endothelia in the peripheral lung and airways occurs during airway hydration, alveolar fluid transport and submucosal gland secretion. Several AQPs are expressed in the lung and airways: AQP1 in microvascular endothelia, AQP3 and AQP4 in airway epithelia, and AQP5 in type I alveolar epithelial cells, submucosal gland acini, and a subset of airway epithelial cells. Phenotype analysis of transgenic knockout mice lacking AQPs has defined their roles in the lung and airways. AQP1 and AQP5 provide the principal route for osmotically driven water transport between airspace and capillary compartments; however, alveolar fluid clearance in the neonatal and adult lung is not affected by their deletion, nor is lung fluid accumulation in experimental models of lung injury. In the airways, though AQP3 and AQP4 facilitate osmotic water transport, their deletion does not impair airway hydration, regulation of airway surface liquid, or fluid absorption. In contrast to these negative findings, AQP5 deletion in submucosal glands reduced fluid secretion by >50%. The substantially slower fluid transport in the lung compared to renal and secretory epithelia probably accounts for the lack of functional significance of AQPs in the lung and airways. Recent data outside of the lung implicating the involvement of AQPs in cell migration and proliferation suggests possible new roles for lung AQPs to be explored.     

Expression and localization of epithelial aquaporins in the adult human lung

Aquaporins (AQPs) facilitate water transport across epithelia and play an important role in normal physiology and disease in the human airways. We used in situ hybridization and immunofluorescence to determine the expression and cellular localization of AQPs 5, 4, and 3 in human airway sections. In nose and bronchial epithelia, AQP5 is expressed at the apical membrane of columnar cells of the superficial epithelium and submucosal gland acinar cells. AQP4 was detected in basolateral membranes in ciliated ducts and by in situ in gland acinar cells. AQP3 is present on basal cells of both superficial epithelium and gland acinus. In these regions AQPs 5, 4, and 3 are appropriately situated to permit transepithelial water permeability. In the small airways (proximal and terminal bronchioles) AQP3 distribution shifts from basal cell to surface expression (i.e., localized to the apical membrane of proximal and terminal bronchioles) and is the only AQP identified in this region of the human lung. The alveolar epithelium has all three AQPs represented, with AQP5 and AQP4 localized to type I pneumocytes and AQP3 to type II cells. This study describes an intricate network of AQP expression that mediates water transport across the human airway epithelium.     

Water permeability through aquaporin-4 is regulated by protein kinase C and becomes rate-limiting for glioma invasion

Glial-derived tumors, gliomas, are highly invasive cancers that invade normal brain through the extracellular space. To navigate the tortuous extracellular spaces, cells undergo dynamic changes in cell volume, which entails water flux across the membrane through aquaporins (AQPs). Two members of this family, AQP1 and AQP4 are highly expressed in primary brain tumor biopsies and both have a consensus phosphorylation site for protein kinase C (PKC), which is a known regulator of glioma cell invasion. AQP4 colocalizes with PKC to the leading edge of invading processes and clustered with chloride channel (ClC2) and K⁺–Cl⁻ cotransporter 1 (KCC1), believed to provide the pathways for Cl⁻ and K⁺ secretion to accomplish volume changes. Using D54MG glioma cells stably transfected with either AQP1 or AQP4, we show that PKC activity regulates water permeability through phosphorylation of AQP4. Activation of PKC with either phorbol 12-myristate 13-acetate or thrombin enhanced AQP4 phosphorylation, reduced water permeability and significantly decreased cell invasion. Conversely, inhibition of PKC activity with chelerythrine reduced AQP4 phosphorylation, enhanced water permeability and significantly enhanced tumor invasion. PKC regulation of AQP4 was lost after mutational inactivation of the consensus PKC phosphorylation site S180A. Interestingly, AQP1 expressing glioma cells, by contrast, were completely unaffected by changes in PKC activity. To demonstrate a role for AQPs in glioma invasion in vivo, cells selectively expressing AQP1, AQP4 or the mutated S180A-AQP4 were implanted intracranially into SCID mice. AQP4 expressing glioma cells showed significantly reduced invasion compared to AQP1 and S180 expressing tumors as determined by quantitative stereology, consistent with a differential role for AQP1 and AQP4 in this process.     

Upregulation of AQP3 and AQP5 induced by dexamethasone and ambroxol in A549 cells

Aquaporins (AQPs) are membrane channel proteins that play roles in the regulation of water permeability in many tissues. AQP1 and AQP5 expressed in lung provide the principal route for osmotically driven water transport. In the airways, AQP3 and AQP4 facilitate water transport. Dexamethasone and ambroxol are often used to treat patients with pulmonary diseases accompanied by airway hypersecretion. The role of AQPs in these effective treatments has not been addressed. In this study, we analyzed the expression of AQPs in a human airway epithelial cell line (A549 cells) and showed that AQP3 and 5, but not AQP1 and 4, were expressed in A549 cells. Both dexamethasone and ambroxol stimulated the expression of AQP3 and 5 at the mRNA and protein levels. The data suggest potential roles of AQP3 and 5 in the regulation of airway hypersecretion, perhaps ultimately providing a target for treating such diseases.