Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics
Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics
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DOI：
10.1038/ki.2008.350
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发表时间：
2008-10-01
影响因子：
19.6
通讯作者：
Norman, Jill T.
中科院分区：
文献类型：
--
作者：
Fine, Leon G.;Norman, Jill T.
在慢性肾脏疾病中，功能损害与肾小管间质纤维化相关，其特征在于炎症、细胞外基质积聚、肾小管萎缩和管周毛细血管稀疏。微血管系统的丧失意味着缺氧环境，并在十年前提出“慢性缺氧假说”作为纤维化进行性的解释时表明缺氧的重要作用。最近的人类数据提供了慢性肾脏疾病中肾氧合降低的证据，而啮齿动物模型中的数据更直接地支持了因果关系，表明肾氧合降低先于基质蓄积，表明缺氧可能引发和促进纤维化反应。事实上，体外研究表明，缺氧可以诱导肾小管间质细胞的促纤维化变化。缺氧在慢性肾脏疾病中的其他假定作用是维持炎症反应，募集，保留和分化为循环祖细胞的促纤维化表型，以及改变内在干细胞群的功能。鉴于积累的数据表明慢性缺氧是终末期肾病的最终常见途径，靶向缺氧的治疗策略可能有利于延缓进展。微血管张力的正常化、给予促血管生成因子以恢复微血管系统的完整性、低氧诱导的转录因子的激活以及低氧介导的祖细胞的靶向和动员都是未来治疗的潜在靶点。现有策略在延缓慢性肾脏疾病方面的有限成功要求探索这些新的治疗途径。
In chronic kidney disease, functional impairment correlates with tubulointerstitial fibrosis characterised by inflammation, accumulation of extracellular matrix, tubular atrophy and rarefaction of peritubular capillaries. Loss of the microvasculature implies a hypoxic milieu and suggested an important role for hypoxia when the "chronic hypoxia hypothesis'' was proposed a decade ago as an explanation for the progressive nature of fibrosis. Recent data in man provide evidence of decreased renal oxygenation in chronic kidney disease while more direct support for a causal role comes from data in rodent models showing that the decline in renal oxygenation precedes matrix accumulation, suggesting hypoxia may both initiate and promote the fibrotic response. Indeed, in vitro studies show that hypoxia can induce pro-fibrotic changes in tubulointerstitial cells. Additional postulated roles for hypoxia in chronic kidney disease are the sustaining of the inflammatory response, the recruitment, retention and differentiation towards a pro-fibrotic phenotype of circulating progenitor cells and the alteration of the function of intrinsic stem cell populations. Given that accumulating data suggests that chronic hypoxia is a final common pathway to end-stage renal disease, therapeutic strategies that target hypoxia may be of benefit in retarding progression. Normalisation of microvascular tone, administration of pro-angiogenic factors to restore microvasculature integrity, activation of hypoxia-inducible transcription factors and hypoxia-mediated targeting and mobilisation of progenitor cells are all potential targets for future therapy. The limited success of existing strategies in retarding chronic kidney disease mandates that these new avenues of treatment be explored.