Hypoxia and Dysregulated Angiogenesis in Kidney Disease

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.