IgA1异常糖基化致IgA肾病肾系膜细胞增殖

IgA肾病是一种常见的原发性肾小球肾炎。IgA肾病的确切发病机制仍不明确。目前的数据表明异常糖基化的IgA1(Gd-IgA1)生产过剩,进而形成循环免疫复合物（IgA1-IC、IgA1-IgG-IC）沉积于肾小球系膜,从而释放细胞因子、诱导炎症反应、激活补体系统导致系膜细胞的增殖以及细胞外基质的增加,进而造成肾小球损伤。     

儿童IgA肾病综合征

1968年Berger氏和Hinglais氏首次叙述了IgA肾病。随后发现过敏性紫癜、肝硬化等许多疾病亦可引起肾小球系膜的IgA沉积,故目前将IgA肾病称之谓IgA肾病综合征。近年来此征发病率显著提高,在美国、英国等某些欧美国家已引起小流行,普遍地认识到IgA肾病是肾小球肾炎最常见类型之一。临床病理特点原发性IgA肾病的特点是系膜区IgA沉积,且常伴有C_3、IgG、IgM和纤维蛋白原的沉积,系膜区肿胀伴有不同程度的急性增生性和节段性硬化病灶,系     

IgA1O-糖基化异常在IgA肾病发病进展中的作用及中医药干预

IgA肾病(Iga nephropathy,IgAN)是一组以IgA或IgA为主的免疫复合物存肾小球系膜区沉积为特征、临床和病理表现多样化,且不伴有系统性损害的最常见原发性肾小球疾病.IgA肾病约占我国原发性肾小球疾病的30%～40%,是亚洲乃至世界范围内最常见的肾脏疾病.     

IgA肾病发病的免疫化学基础——IgA的免疫生物学

系膜IgA肾病(IgAN)是临床上最常见的原发性肾小球疾病之一,阐明其发病机理是近20年来重点研究的课题。IgAN的主要病理特征为肾小球系膜区IgA的沉积,IgAN患者的肾活检标本中免疫复合物(IC)洗脱物用蔗糖密度梯度离心和与分泌片结合能力测定等方法证实,沉积在肾小球的IgA为多聚IgA(PIgA)。体内或体外实验均证实单体IgA(mIgA)不会沉积在肾小球引起肾炎,动物实验也证实     

杨霓芝教授治疗系膜增生性肾小球肾炎的临证经验

系膜增生性肾小球肾炎（mesangial proliferative glomerulonephritis,MsPGN）是一种以弥漫性肾小球系膜细胞增生及不同程度系膜基质增多为主要病理特征的原发性肾小球疾病。据其免疫病理可将其分为IgA肾病（以IgA沉积为主）及非IgA肾病两大类。     

IgA肾病研究新进展

IgA肾病是最常见的原发性肾小球性肾炎,最新定义为自体肾活检组织免疫荧光或免疫酶标染色显示以IgA或IgA沉积为主的肾小球疾病（不要求所有肾小球均有IgA沉积）,同时除外狼疮性肾炎等继发性IgA沉积。IgA沉积须有一定强度,分布于系膜区,可伴有或不伴有毛细血管袢沉积。除外单纯膜性、弥漫、球性、颗粒状或线状肾小球基底膜（GBM）沉积。     

IgA肾病肾组织CD_（71）表达与病理类型的关系

IgA肾病（IgA nephropathy,IgAN）是我国最常见的原发性肾小球疾病,指IgA或以IgA为主的免疫球蛋白弥漫沉积在肾小球系膜区及毛细血管袢引起的一系列临床症状及病理改     

IgA肾病的治疗

IgA肾病，是以IgA为主的免疫球蛋白在肾小球系膜区弥漫沉积所致的肾小球损害。不难看出，IgA肾病系免疫病理学诊断名词，即肾活检组织经免疫荧光染色，在肾小球系膜区可见IgA为主的免疫球蛋白颗粒状沉积，常伴有C3沉积，而少见补体的前期产物如C1q和C4的沉积。     

IgA1 O-糖基化异常在IgA肾病发病进展中的作用及中医药干预

IgA肾病（IgA nephropathy,IgAN）是一组以IgA或IgA为主的免疫复合物在肾小球系膜区沉积为特征、临床和病理表现多样化,且不伴有系统性损害的最常见原发性肾小球疾病。IgA肾病约占我国原发性肾小球疾病的30％-40％,是亚洲乃至世界范围内最常见的肾脏疾病。     

IgA肾病的病理与临床

IgA肾病（IgA nephropathy）是我国最常见的肾小球疾病,约占原发肾小球疾病的30％～40％。自从40多年前Berger首次报道IgA肾病以来,越来越多的学者认为IgA肾病不是单一疾病,而是一组以IgA为主的免疫球蛋白颗粒状弥漫沉积在肾小球系膜区及毛细血管袢的临床综合征。IgA肾病的临床表现可从无症状镜下血尿伴或不伴有蛋白尿到典型肾病综合征,或严重的急进性肾炎综合征,     

Platelet-derived growth factor mesangial deposits in mesangial IgA glomerulonephritis

Platelets may play a role in the pathogenesis of IgA glomerulonephritis (IgAGN). Ultrastructural labelling of platelet antigens might identify activated platelets, and localisation of platelet antigens may assist in understanding the role of platelets in glomerular disease. We examined renal biopsies from eight patients with mesangial IgAGN using protein A-gold immunoelectron microscopy. Serial sections were stained with antisera against platelet-derived growth factor (PDGF), platelet factor 4, beta-thrombolglobulin, platelet glycoprotein IIb-IIIa complex, and fibrinogen, as well as antisera against IgA, IgG, IgM and C3c. Platelets, including activated and degranulated platelets, were detected in capillaries in five of eight biopsies. PDGF was detected in mesangial deposits in five of eight cases. In one case immunolabelling was as intense as IgA labelling. Fibrinogen labelling was present in six of eight. Less intense labelling or negative results were obtained with the other antisera. There was no correlation between intensity of immunolabelling and any clinical or morphological features reflecting severity of glomerular lesions. The role of platelets in the pathogenesis of IgAGN remains unclear. The documentation of frequent deposit of PDGF should stimulate further interest in PDGF participation in this condition.     

Caveolae in mesangial cells and caveolin expression in mesangial proliferative glomerulonephritis

BACKGROUND: Caveolae are plasma membrane invaginations that have a diameter of 40 to 60 nm. Recent evidences have demonstrated that caveolae contain a variety of signal transduction molecules. Caveolin is a marker protein of caveolae and has been proposed to play a negative regulatory role in signal transduction. The aim of this study was to investigate the behavior of caveolae and caveolin in experimental glomerulonephritis, the localization of both platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) receptors in the caveolae membrane, and the regulation of caveolin expression in cultured mesangial cells. METHODS: The expression of caveolin-1 was examined by immunoblotting and immunohistology using anti-caveolin antibody in anti-Thy-1 nephritis. The caveolae membrane fraction of mesangial cells was isolated by sucrose gradient method and expression of PDGF receptor and TGF-beta receptor were detected by immunoblotting. The effects of mitogens such as phorbol 12-myristate 13-acetate (PMA) and PDGF on the expression of caveolin-1 protein and mRNA were also examined in cultured mesangial cells. RESULTS: Caveolin-1 was mainly expressed in glomeruli and was significantly up-regulated in anti-Thy-1 nephritis rat kidney. In cultured mesangial cells, the membrane invaginations of caveolae were revealed by electron microscopy. PDGF receptors abounded in the caveolae membrane and rapidly changed their subcellular distribution after ligand stimulation. In contrast, TGF-beta receptors abounded in the non-caveolae membrane and did not change after ligand stimulation. Decreases in caveolin-1 protein, which were associated with increases in mRNA expression after the exposure of PMA or PDGF-BB, suggested an increased turnover of caveolin-1 in mesangial cells stimulated by mitogens. CONCLUSION: To our knowledge, this electron microscopical study is the first to demonstrate the presence of caveolae in cultured mesangial cells. Caveolae integrate PDGF receptors, and caveolin-1 may play a role in the pathogenesis of the mesangial proliferative glomerular diseases through PDGF signaling.     

Heparin decreases mesangial matrix accumulation after selective antibody-induced mesangial cell injury.

Anti-rat thymocyte antibody-induced injury of glomerular mesangial cells is characterized initially by lysis (1 h) and is followed by proliferation (beginning at 3 to 4 days), with resolution that can include a focal increase in mesangial matrix (by 28 days). Chronic administration (every 12 h) of heparin (anticoagulant or nonanticoagulant) resulted in a decrease in antibody-induced mesangial cell proliferation, which, in turn, was associated with a decrease in the size and number of areas of focal mesangial matrix increase. The effect could not be attributed to the effect of heparin on complement, to alterations in the small numbers of la-positive cells that characterize the lesion, or to binding of antibody to glomeruli. The beneficial effects of heparin in reducing mesangial cell proliferation, with a subsequent reduction in matrix increase, suggest that mesangial cell responses are a major element in the development of at least some forms of glomerulosclerosis. The possible mechanisms by which these effects of heparin may be achieved are discussed.     

Chemoattractants provoke monocyte adhesion to human mesangial cells and mesangial cell injury.

Infiltration of glomerular mesangium by monocytes/macrophages is a prominent pathologic finding in many forms of glomerulonephritis (GN). While the mechanism(s) by which infiltration occurs is incompletely understood, monocyte adhesion to glomerular endothelial cells, provoked by inflammatory mediators, appears to be an important early step. In the present study, we assessed the influence of chemotactic peptides (C5a) and lipids (LTB4 and PAF) on adhesion of human monocytes and mesangial cells, to determine if mesangial cells (glomerular pericytes with smooth muscle properties) represent potential targets for adhesion of chemoattractant-activated monocytes following their diapedesis from the intravascular space. C5a and LTB4 provoked rapid (onset less than 1 min) monocyte-mesangial cell adhesion at nanomolar concentrations via actions with monocytes, while PAF was less potent in this regard. Monoclonal antibodies (mAb) were used to define the monocyte and mesangial cell adhesion molecules involved in these interactions. C5a- and LTB4-induced monocyte adhesion was inhibited (approximately 54%) by mAb against the common beta CD18 subunit of CD11/CD18 leukocyte integrins, while mAb against monocyte L-selectin was without effect. MAb against unique CD11 subunits were used to determine the relative contributions of different CD11/CD18 integrins. In this regard, adhesion was inhibited by mAb against CD11b (approximately 41%), and CD11c (approximately 23%), but not CD11a. MAb against mesangial cell ICAM-1 afforded approximately 27% reduction in adhesion, while mAb against VCAM-1, E-selectin, and P-selectin were without effect. GM-CSF, a cytokine generated by monocytes and mesangial cells, also provoked CD11/CD18-dependent adhesion, and primed monocytes to the actions of chemoattractants.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nonenzymatic glycosylation of mesangial matrix on proliferation of mesangial cells.

Cross-linking of cell matrix components by nonenzymatic glycosylation may contribute to diabetic glomerulopathy. We examined the effects of modification of matrix by nonenzymatic glycosylation on mesangial cell function. Matrix was generated by growing mesangial cells in tissue culture for 2 wk and removing the cells with a detergent cell-lysis solution. By indirect immunofluorescence and Northern-blot analysis, the remaining matrix contained laminin, fibronectin, and collagens type I and IV. The matrix was modified by incubation for 24 h with 50 mM glycolaldehyde, a highly reactive cross-linking nonenzymatic glycosylation product, or for 2 wk with 200 mM glucose-6-phosphate (G6P). Modification was carried out with or without equimolar aminoguanidine, an inhibitor of cross-link formation. Nonenzymatic glycosylation of the matrix by glycolaldehyde or G6P was confirmed by fluorometry and [14C]G6P incorporation and was prevented by aminoguanidine. [3H]thymidine incorporation for 24 h by mesangial cells plated onto unmodified or modified matrix was then performed. Modification of matrix had no effect on attachment of mesangial cells, determined 4 h after plating. Nonenzymatic glycosylation of matrix by glycolaldehyde or G6P significantly inhibited thymidine incorporation by mesangial cells. This effect was partially reversible by aminoguanidine. Aminoguanidine-modified matrix had no effect on thymidine incorporation. Thymidine-incorporation results were confirmed by direct cell counting. We conclude that modification of matrix by nonenzymatic glycosylation influences growth of mesangial cells, which could contribute to the mesangial abnormalities of diabetic glomerulopathy.     

Regulation of mesangial cell proliferation

Mesangial cell proliferation constitutes a frequent finding in a number of glomerular diseases that progress to glomerular sclerosis. The factors responsible for mesangial cell growth regulation in vivo are ill defined. However, cell culture data indicate that an array of mediators may have mitogenic or antimitogenic effects on these cells. This brief review discusses the relevance of selected factors such as platelet-derived growth factor (PDGF) in this context. In vitro data indicate that PDGF is one of the most potent mesangial cell mitogens, that it may have autoregulatory properties, and that it may represent the final common pathway for a number of other mitogenic peptides. In contrast to PDGF, the relevance of inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF) or interleukin-6 (IL-6) for mesangial cell proliferation is less evident, with growth-inhibitory to weakly growth-promoting effects on mesangial cells. Transforming growth factor beta (TGF beta) appears to be unique in that it has a concentration-dependent mitogenic or antimitogenic effect on mesangial cells. Prostaglandins may also have variable effects, ranging from mitogenic (PGE2 alpha) to growth inhibitory (PGI2, PGF2, TxA2). These data support the notion that mesangial cell growth in vivo is regulated by a complex network of synergistic or antagonistic growth factors. The relative importance of each of these growth factors in the in vivo situation will have to be elucidated by future studies using specific receptor antagonists or neutralizing antibodies.