Tipping the Balance from Angiogenesis to Fibrosis in Chronic Kidney Disease

  • Yosuke Hirakawa
  • Tetsuhiro Tanaka
  • Masaomi NangakuEmail author
Part of the Molecular and Translational Medicine book series (MOLEMED)


The kidneys are innately under a low oxygen tension condition that originates from their unique and complicated vasculature. In chronic kidney disease (CKD), renal hypoxia occurs, and peritubular capillary rarefaction contributes to renal hypoxia. Interventions to angiogenic factors such as vascular endothelial growth factor (VEGF) and angiopoietin affect the development or maintenance of normal kidney structure. VEGF is mainly excreted from tubular cells and affects both endothelial cells and podocytes. Both low and high VEGF levels are injurious to the kidney; insufficient VEGF results in endothelial dysfunction, while excessive VEGF damages the glomeruli in a manner resembling diabetic kidney disease (DKD). The importance of angiopoietins is shown in atherosclerosis in CKD in both clinical patients and experimental animal models, while evidence of the effect of angiopoietins on CKD progression remains limited. Another important player is hypoxia. Clinical epidemiology findings have shown that renal hypoxia is involved in the pathogenesis and progression of CKD. Hypoxia-inducible factors (HIFs) govern the cellular response to hypoxia and have both angiogenetic and fibrogenic effects. The administration of VEGF, a HIF stabilizer, or progenitor cells leads to peritubular capillary maintenance, followed by renal fibrosis alleviation. Indoxyl sulfate is a representative uremic toxin and pathological factor that causes the imbalance between angiogenesis and fibrosis and subsequent insufficient HIF activation. The treatment of uremic toxins has the potential to adjust this angiogenesis–fibrosis imbalance.


Chronic kidney disease Angiogenesis Fibrosis Hypoxia Hypoxia-inducible factor Vascular endothelial growth factor Angiopoietin 


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Yosuke Hirakawa
    • 1
  • Tetsuhiro Tanaka
    • 1
  • Masaomi Nangaku
    • 1
    Email author
  1. 1.Division of Nephrology and EndocrinologyThe University of Tokyo School of MedicineTokyoJapan

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