Fine Leon G, Norman Jill T
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Kidney Int. 2008 Oct;74(7):867-72. doi: 10.1038/ki.2008.350. Epub 2008 Jul 16.
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.
在慢性肾脏病中，功能损害与肾小管间质纤维化相关，其特征为炎症、细胞外基质积聚、肾小管萎缩以及肾小管周围毛细血管稀疏。微血管的丧失意味着缺氧环境，并且在十年前提出“慢性缺氧假说”以解释纤维化的进展性质时，提示了缺氧的重要作用。近期人体研究数据证明了慢性肾脏病中肾脏氧合作用降低，而啮齿动物模型数据提供了更直接的因果关系证据，表明肾脏氧合作用下降先于基质积聚，提示缺氧可能启动并促进纤维化反应。事实上，体外研究表明缺氧可诱导肾小管间质细胞发生促纤维化变化。缺氧在慢性肾脏病中的其他假定作用包括维持炎症反应、使循环祖细胞募集、滞留并分化为促纤维化表型，以及改变内在干细胞群的功能。鉴于越来越多的数据表明慢性缺氧是终末期肾病的最终共同途径，针对缺氧的治疗策略可能有助于延缓疾病进展。微血管张力正常化、给予促血管生成因子以恢复微血管完整性、激活缺氧诱导转录因子以及缺氧介导的祖细胞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病方面成效有限，这就要求探索这些新的治疗途径。
