Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Kidney Dis (Basel). 2015 May;1(1):80-9. doi: 10.1159/000381515. Epub 2015 Apr 15.
Accumulating evidence has demonstrated that renal hypoxia has a crucial role in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and AKI-to-CKD transition, ultimately culminating in end-stage kidney disease. Renal hypoxia in progressive CKD is intricately linked to persisting capillary loss, which is mainly due to dysregulated angiogenesis.
In CKD, hypoxia-inducible factor (HIF) accumulates in the ischemic tubulointerstitium but fails to sufficiently stimulate angiogenic responses, partly because of blunted activation of HIF, which is best exemplified in diabetic kidney disease. In addition, vascular endothelial growth factor (VEGF) expression is downregulated, possibly because injured tubules are not able to express sufficient VEGF and inflammatory circumstances inhibit VEGF expression. The upregulation of antiangiogenic factors and the incompetence of endothelial progenitor cells (EPCs) may also play some roles in the inadequacy of capillary restoration. Administration of VEGF or angiopoietin-1 maintains peritubular capillaries in several kidney diseases; however, administration of a single angiogenic factor may lead to the formation of abnormal vessels and induce inflammation, resulting in worsening of hypoxia and tubulointerstitial fibrosis. HIF stabilization, which aims to achieve the formation of mature and stable vessels by inducing coordinated angiogenesis, is a promising strategy. Given that the effect of systemic HIF activation is highly context-dependent, further studies are needed to elucidate the precise roles of HIF in various kidney diseases. The adoptive transfer of EPCs or mesenchymal stem cells (MSCs) is a fascinating alternative strategy to restore the peritubular capillaries.
Suppressed HIF activation and VEGF expression may be responsible for the dysregulated angiogenesis in progressive CKD. Administration of a single angiogenic factor can cause abnormal vessel formation and inflammation, leading to a detrimental result. Although further studies are warranted, HIF stabilization and adoptive transfer of EPCs or MSCs appear to be promising strategies to restore normal capillaries.
越来越多的证据表明，肾脏缺氧在急性肾损伤（AKI）、慢性肾脏病（CKD）和 AKI 向 CKD 转变的发病机制中起着关键作用，最终导致终末期肾病。进展性 CKD 中的肾缺氧与持续的毛细血管丧失密切相关，而毛细血管丧失主要是由于血管生成失调。
在 CKD 中，缺氧诱导因子（HIF）在缺血的肾小管间质中积累，但不能充分刺激血管生成反应，部分原因是 HIF 的激活减弱，在糖尿病肾病中表现得最为明显。此外，血管内皮生长因子（VEGF）的表达下调，可能是因为受损的肾小管不能表达足够的 VEGF，炎症环境抑制了 VEGF 的表达。抗血管生成因子的上调和内皮祖细胞（EPCs）的功能不全也可能在毛细血管修复不足中发挥一定作用。在几种肾脏疾病中，给予 VEGF 或血管生成素-1 可维持肾小管周围毛细血管；然而，给予单一的血管生成因子可能导致异常血管的形成，并引发炎症，导致缺氧和肾小管间质纤维化加重。HIF 稳定化旨在通过诱导协调的血管生成来实现成熟和稳定的血管形成，这是一种很有前途的策略。鉴于系统性 HIF 激活的效果高度依赖于具体情况，需要进一步研究以阐明 HIF 在各种肾脏疾病中的确切作用。EPCs 或间充质干细胞（MSCs）的过继转移是恢复肾小管周围毛细血管的一种很有吸引力的替代策略。
抑制的 HIF 激活和 VEGF 表达可能是进展性 CKD 中血管生成失调的原因。给予单一的血管生成因子可导致异常血管形成和炎症，导致不良后果。虽然还需要进一步的研究，但 HIF 稳定化和 EPCs 或 MSCs 的过继转移似乎是恢复正常毛细血管的有前途的策略。
