Journal
CELLULAR SIGNALLING
Volume 69, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2020.109524
Keywords
Autosomal dominant polycystic kidney disease, ADPKD; Polycystic kidney disease, PKD; Hypoxia; Hypoxia-inducible factor, HIF
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Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [387509280, SFB 1350, 394046635, SFB 1365]
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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 feed-forward 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.
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