Hypoxia and Dysregulated Angiogenesis in Kidney Disease

Abstract

Background: 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. Summary: 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. Key Messages: 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.

Hypoxia and hypoxia-inducible factors in chronic kidney disease

“…Although HIF likely upregulates angiogenic factors, such as VEGF, that theoretically leads to the restoration of capillary densities, this adaptation mechanism usually fails; thus, capillary rarefaction is sustained and progressive. Several possibilities have been suggested to explain the failure of capillary restoration [59]. First, VEGF expression in the kidney is decreased in CKD, which may indicate that damaged tubular epithelial cells do not produce sufficient VEGF [60].…”

Endothelial cell functions impaired by interferon in vitro: Insights into the molecular mechanism of thrombotic microangiopathy associated with interferon therapy

“…Consistent with their reports, we observed no changes of vWF expression on endothelial cell surface after exposure to IFNs. Furthermore, since dysregulated angiogenesis is associated with kidney disease [49], IFN-induced angiostasis could negatively influence glomerular function resulting from imbalance between peritubular capillary formation and regression, which worsens vascular complications and nephrotic syndrome in patients.…”

Integrative View of the Mechanisms that Induce Acute Kidney Injury and its Transition to Chronic Kidney Disease

“…Vascular endothelial growth factor (VEGF) is required for the maintenance of the peritubular capillaries' homeostasis. VEGF is expressed in podocytes, proximal tubule, and thick ascending loop, while the VEGF receptors 1 and 2 are located in endothelial cells, and peritubular and glomerular capillaries 15,16 . AKI is accompanied by endothelium cell damage, which is characterized by the alteration of the actin cytoskeleton, causing the detachment of endothelial monolayer cells and affecting the tight intercellular junctions which, in turn, increase vascular permeability and the production of edema.…”

“…In addition, in vitro studies have linked hypoxia to the inflammatory process because it induces leukocyte adhesion to the endothelium through the activation of β2 integrin 67 . It is not entirely clear how vascular rarefaction and chronic hypoxia persist because hypoxiainducible factor (HIF) must be activated and initiates the induction of multiple angiogenic factors to stimulate a vascular compensatory response; however, this mechanism is not well activated and almost always is not sufficient to avoid vascular rarefaction 15 .…”