Hypoxia-induced changes in extracellular matrix metabolism in renal cells.

J T Norman, C Orphanides, P Garcia, L G Fine
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引用次数: 83

Abstract

The mechanisms underlying the progressive fibrosis that characterises end-stage renal disease in vivo remain to be established but hypoxia, as a result of microvascular injury and loss, has been suggested to play an important role. In support of this hypothesis, in vitro studies show that hypoxia (1% O2) induces a fibrogenic phenotype in human renal tubular endothelia, interstitial fibroblasts and microvascular endothelial cells, simultaneously increasing extracellular matrix (ECM) production and decreasing turnover via effectors on matrix-degrading enzymes and their inhibitors. The effects of hypoxia on ECM metabolism are independent of hypoxia-induced growth factors and are mediated by a haem-protein sensor and activation of both protein kinase C- and tyrosine kinase-mediated signal transduction pathways. De novo gene transcription is regulated by both hypoxia-inducible factor-1-dependent and -independent mechanisms. Further understanding of the molecular mechanisms by which decreased oxygen alters expression of genes involved in ECM metabolism in renal cells may provide new insights into the pathogenesis of fibrosis and identify novel avenues for intervention.
缺氧诱导肾细胞胞外基质代谢的变化。
作为终末期肾脏疾病特征的进行性纤维化的体内机制仍有待确定,但微血管损伤和丧失导致的缺氧已被认为在其中发挥了重要作用。为了支持这一假设,体外研究表明,缺氧(1% O(2))可诱导人肾小管内皮、间质成纤维细胞和微血管内皮细胞的成纤维表型,同时通过基质降解酶及其抑制剂的效应物增加细胞外基质(ECM)的产生并减少周转。缺氧对ECM代谢的影响不依赖于缺氧诱导的生长因子,而是由血红蛋白传感器和蛋白激酶C和酪氨酸激酶介导的信号转导途径的激活介导。新生基因转录受缺氧诱导因子-1依赖性和非依赖性机制的调控。进一步了解氧气减少改变肾细胞中参与ECM代谢的基因表达的分子机制,可能为纤维化的发病机制提供新的见解,并确定新的干预途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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