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

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.