Global gene expression analysis reveals a role for the α1 integrin in renal pathogenesis
Global gene expression analysis reveals a role for the α1 integrin in renal pathogenesis
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DOI：
10.1074/jbc.m102859200
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发表时间：
2001-09-07
影响因子：
4.8
通讯作者：
Gotwals, P
中科院分区：
文献类型：
--
作者：
Sampson, NS;Ryan, ST;Gotwals, P
肾纤维化是大多数进行性肾脏疾病的标志，包括遗传性疾病阿尔波特综合征。我们使用微芯片阵列对阿尔波特综合征小鼠肾脏进行基因表达分析，以表征纤维化的发展。除了基质和基质重塑基因，与间质纤维化一致，巨噬细胞相关基因在Alport综合征肾脏中表达水平升高。肾切片免疫组化分析显示，巨噬细胞和肌成纤维细胞在肾小管间质中积聚。α(1)整合素的缺失导致Alport综合征小鼠小管间质中肌成纤维细胞和巨噬细胞的积累减少，并延缓疾病进展。转化生长因子-拮抗剂虽然能减少间质纤维化，但不能限制巨噬细胞在小管间质中的积聚和疾病进展。在这项研究中，我们发现了以前被忽视的发生在小管间质区域的炎症事件。我们提出，除了先前提出的α (1) β(1)整合素在系膜扩张和层粘连蛋白异常沉积中的作用外，该整合素可能对单核细胞积聚至关重要，而单核细胞积聚反过来可能直接导致肾功能衰竭。我们的基因表达和免疫组织化学数据表明，巨噬细胞的积累依赖于巨噬细胞表面α(1)整合素的表达，抗α(1)整合素策略可以作为治疗慢性炎症和纤维化疾病的治疗方法。
Kidney fibrosis is the hallmark of most types of progressive kidney disease, including the genetic disorder Alport's syndrome. We undertook gene expression analysis in Alport's syndrome mouse kidneys using microchip arrays to characterize the development of fibrosis. La addition to matrix and matrix-remodeling genes, consistent with interstitial fibrosis, macrophage-related genes show elevated expression levels in Alport's syndrome kidneys. Immunohistochemical analysis of kidney sections illustrated that macrophages as well as myofibroblasts accumulate in the tubular interstitium. Deletion of alpha (1) integrin results in decreased accumulation of both myofibroblasts and macrophages in the tubular interstitium in Alport's syndrome mice and delays disease progression. Transforming growth factor beta antagonism, although reducing interstitial fibrosis, does not limit macrophage accumulation in the tubular interstitium and disease progression. In this study, we identified previously overlooked inflammatory events that occur in the tubulointerstitial region. We propose that in addition to the previously suggested role for the alpha (1)beta (1) integrin in mesangial expansion and abnormal laminin deposition, this integrin may be critical for monocyte accumulation that, in turn, may lead directly to renal failure. Our gene expression and immunohistochemical data indicate that macrophage accumulation is dependent on alpha (1) integrin expression on the macrophage cell surface and that anti-alpha (1) integrin strategies may be employed as therapeutics in the treatment of chronic inflammatory and fibrotic diseases.