Growth factor expression in a murine model of cryoglobulinemia
Growth factor expression in a murine model of cryoglobulinemia
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DOI：
10.1046/j.1523-1755.2003.00778.x
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发表时间：
2003-02-01
影响因子：
19.6
通讯作者：
Segerer, S
中科院分区：
文献类型：
--
作者：
Taneda, S;Hudkins, KL;Segerer, S
背景。包括血小板衍生生长因子（PDGF）和转化生长因子- β (tgf - β)在内的生长因子的表达增加被认为在系膜扩张和肾小球硬化中起关键作用。胸腺基质淋巴生成素（TSLP）转基因小鼠发生混合冷球蛋白血症和膜增生性肾小球肾炎（MPGN）。在此，我们描述了PDGF和tgf - β异构体的肾脏表达与细胞外基质（ECM）成分和细胞增殖和活化标志物的变化之间的关系。按规定的时间间隔处死123只小鼠，其中TSLP转基因小鼠61只，野生型小鼠62只。原位杂交分析PDGF- a链、-b链、PDGF α和β受体（β -r）和tgf - β a1 mRNA。通过免疫组织化学检测α -平滑肌肌动蛋白（alphaSMA）、I型胶原、IV型胶原、层粘连蛋白和增殖细胞标志物（PCNA）的表达。同时，采用免疫组化和原位杂交的方法对载玻片进行研究，采用识别单核细胞/巨噬细胞的抗体和检测PDGF b链、PDGF β - r或tgf - β 1 mrna的核探针。增生的肾小球细胞数量增加出现在病程早期，与alphaSMA的新生表达有关。TSLP转基因小鼠系膜和壁上皮细胞中PDGF b链和β - r mRNA表达增加，并与PCNA阳性细胞数相关。tgf - β 1 mRNA表达增加与IV型胶原沉积平行。显著比例的Mac-2阳性巨噬细胞表达TGF-beta1 mRNA，而只有一小部分肾小球巨噬细胞表达PDGF b链mRNA。巨噬细胞未检测到PDGF β - r mRNA的表达。TSLP转基因小鼠发生膜增生性肾小球肾炎，肾小球细胞增殖和基质沉积与PDGF b链、PDGF β - r和tgf - β - 1表达增加有关。这些发现扩展了覆盖这些生长因子的范式，这些生长因子建立在大鼠肾系膜溶解模型和修复小鼠进行性肾小球肾炎模型中，与人类MPGN非常相似。
Background. Increased expression of growth factors including platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are thought to play pivotal roles during mesangial expansion and glomerulosclerosis. Thymic stromal lymphopoietin (TSLP) transgenic mice develop mixed cryoglobulinemia and a membranoproliferative glomerulonephritis (MPGN). Here we describe the renal expression of isoforms of PDGF and TGF-beta in relation to changes in extracellular matrix (ECM) components and markers of cell proliferation and activation in this model.Methods. A total of 123 mice, including 61 TSLP transgenic mice and 62 wild-type controls, were sacrificed at defined intervals. PDGF-A chain, -B chain, PDGF alpha- and beta-receptor (beta-R) and TGF-beta1 mRNA were analyzed by in situ hybridization. Expression of alpha smooth muscle actin (alphaSMA), collagen type I, collagen type IV, laminin, and a marker of proliferating cells (PCNA) were assessed by immunohistochemistry. Slides also were studied by combined immunohistochemistry and in situ hybridization with an antibody that recognizes monocytes/macrophage and with riboprobes that detect PDGF B-chain, PDGF beta-R or TGF-beta1 mRNA.Results. Increased numbers of proliferating glomerular cells appeared early in the disease course, associated with de novo expression of alphaSMA. Expression of PDGF B-chain and beta-R mRNA was increased in the mesangium and in parietal epithelial cells of TSLP transgenic mice and correlated with the number of PCNA positive cells. Increased TGF-beta1 mRNA expression paralleled the deposition of type IV collagen. A significant proportion of Mac-2 positive macrophages expressed TGF-beta1 mRNA, while only a small percentage of glomerular macrophages expressed PDGF B-chain mRNA. No PDGF beta-R mRNA expression by macrophages was detected.Conclusion. TSLP transgenic mice develop a membranoproliferative glomerulonephritis in which glomerular cell proliferation and matrix deposition are associated with an increased expression of PDGF B-chain, PDGF beta-R and TGF-beta1. These findings extend the paradigms covering these growth factors established in the rat Thy 1 model of mesangiolysis and repairs to a murine model of progressive glomerulonephritis closely resembling human MPGN.