Role for transforming growth factor-β1 in Alport renal disease progression
Role for transforming growth factor-β1 in Alport renal disease progression
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DOI：
10.1046/j.1523-1755.1999.00744.x
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发表时间：
1999-11-01
影响因子：
19.6
通讯作者：
Cosgrove, D
中科院分区：
文献类型：
--
作者：
Sayers, R;Kalluri, R;Cosgrove, D
背景Alport综合征由α 3（IV）、α 4（IV）或α 5（IV）胶原基因突变引起。这种疾病的特征是进行性肾小球肾炎，通常伴有高频感音神经性听力损失。产生并表征了Alport综合征常染色体形式[胶原蛋白α 3（IV）敲除]的小鼠模型。在这项研究中，该模型被用来证明转化生长因子β 1（TGF-β 1）在Alport肾病发病机制中的潜在作用。在肾脏疾病进展过程中的不同阶段取正常和Alport小鼠的肾脏，通过北方印迹、原位杂交和免疫组织学分析TGF-β 1和细胞外基质组分的表达。用RNase保护法检测正常和Alport人肾脏TGF-β 1的表达。编码TGF-β 1（小鼠和人）、巢蛋白、纤连蛋白和胶原α 1（IV）和α 2（IV）链的mRNA在总肾脏中显著诱导，作为Alport肾病进展的函数。在患有晚期疾病的动物的肾小球足细胞中观察到这些特异性mRNA的诱导。第10周时肾小管上皮细胞中IV型胶原、层粘连蛋白-1和纤连蛋白明显升高，但第6周时没有，提示北方印迹上特异性mRNA表达升高反映了与肾小管间质纤维化相关的事件。编码TGF-β 1和细胞外基质成分的mRNA在患病肾脏的足细胞中的伴随积累可能反映了Alport肾病进展中的关键事件。这些数据表明TGF-β 1在Alport综合征相关的肾小球和肾小管间质损伤中的作用。
Background. Alport syndrome results from mutations in either the alpha 3(IV), alpha 4(IV), or alpha 5(IV) collagen genes. The disease is characterized by a progressive glomerulonephritis usually associated with a high-frequency sensorineural hearing loss. A mouse model for an autosomal form of Alport syndrome [collagen alpha 3(IV) knockout] was produced and characterized. In this study, the model was exploited to demonstrate a potential role for transforming growth factor-beta 1 (TGF-beta 1) in Alport renal disease pathogenesis.Method's. Kidneys from normal and Alport mice, taken at different stages during the course of renal disease progression, were analyzed by Northern blot, in situ hybridization, and immunohistology for expression of TGF-beta 1 and components of the extracellular matrix. Normal and Alport human kidney was examined for TGF-beta 1 expression using RNase protection.Results. The mRNAs encoding TGF-beta 1 (in both mouse and human), entactin, fibronectin, and the collagen alpha 1(IV) and alpha 2(IV) chains were significantly induced in total kidney as a function of Alport renal disease progression. The induction of these specific mRNAs was observed in the glomerular podocytes of animals with advanced disease. Type IV collagen, laminin-1, and fibronectin were markedly elevated in the tubulointerstitium at 10 weeks, but not at 6 weeks, suggesting that elevated expression of specific mRNAs on Northern blots reflects events associated with tubulointerstitial fibrosis.Conclusions. The concomitant accumulation of mRNAs encoding TGF-beta 1 and extracellular matrix components in the podocytes of diseased kidneys may reflect key events in Alport renal disease progression. These data suggest a role for TGF-beta 1 in both glomerular and tubulointerstitial damage associated with Alport syndrome.