Role of oxygen and the HIF-pathway in polycystic kidney disease

Cell Signal. 2020 May;69:109524. doi: 10.1016/j.cellsig.2020.109524. Epub 2020 Jan 2.


Kidney cyst growth in ADPKD is associated with regional hypoxia, presumably due to a mismatch between enlarged cysts and the peritubular capillary blood supply and compression of peritubular capillaries in cyst walls. Regional hypoxia leads to activation of hypoxia-inducible transcription factors, with the two main HIF isoforms, HIF-1 and HIF-2 expressed in cyst epithelia and pericystic interstitial cells, respectively. While HIF-2 activation is linked to EPO production, mitigating the anemia that normally accompanies chronic kidney disease, HIF-1 promotes cyst growth. HIF-dependent cyst growth is primarily due to an increase in chloride-dependent fluid secretion into the cyst lumen. However, given the broad spectrum of HIF-target genes, additional HIF-mediated pathways may also contribute to cyst progression. Furthermore, hypoxia can influence cyst growth through the generation of reactive oxygen species. Since cyst expansion aggravates regional hypoxia, a feedforward loop is established that accelerates cyst expansion and disease progression. Inhibiting the HIF pathway and/or HIF target genes that are of particular relevance for HIF-dependent cyst fluid secretion may therefore represent novel therapeutic approaches to retard the progression of APDKD.

Keywords: Autosomal dominant polycystic kidney disease, ADPKD; Hypoxia; Hypoxia-inducible factor, HIF; Polycystic kidney disease, PKD.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cysts / metabolism
  • Cysts / pathology
  • Humans
  • Hypoxia* / metabolism
  • Hypoxia* / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Kidney / metabolism
  • Kidney / pathology
  • Oxygen / metabolism*
  • Polycystic Kidney, Autosomal Dominant* / metabolism
  • Polycystic Kidney, Autosomal Dominant* / pathology


  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • endothelial PAS domain-containing protein 1
  • Oxygen