Hypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD)

Am J Physiol Renal Physiol. 2011 May;300(5):F1235-43. doi: 10.1152/ajprenal.00348.2010. Epub 2011 Jan 26.


Cyst expansion in polycystic kidney disease (PKD) results in localized hypoxia in the kidney that may activate hypoxia-inducible factor-1α (HIF-1α). HIF-1α and autophagy, a form of programmed cell repair, are induced by hypoxia. The purposes were to determine HIF-1α expression and autophagy in rat and mouse models of PKD. HIF-1α was detected by electrochemiluminescence. Autophagy was visualized by electron microscopy (EM). LC3 and beclin-1, markers of autophagy, were detected by immunoblotting. Eight-week-old male heterozygous (Cy/+) and 4-wk-old homozygous (Cy/Cy) Han:SPRD rats, 4-wk-old cpk mice, and 112-day-old Pkd2WS25/- mice with a mutation in the Pkd2 gene were studied. HIF-1α was significantly increased in massive Cy/Cy and cpk kidneys and not smaller Cy/+ and Pkd2WS25/- kidneys. On EM, features of autophagy were seen in wild-type (+/+), Cy/+, and cpk kidneys: autophagosomes, mitophagy, and autolysosomes. Specifically, autophagosomes were found on EM in the tubular cells lining the cysts in cpk mice. The increase in LC3-II, a marker of autophagosome production and beclin, a regulator of autophagy, in Cy/Cy and cpk kidneys, followed the same pattern of increase as HIF-1α. To determine the role of HIF-1α in cyst formation and/or growth, Cy/+ rats, Cy/Cy rats, and cpk mice were treated with the HIF-1α inhibitor 2-methoxyestradiol (2ME2). 2ME2 had no significant effect on kidney volume or cyst volume density. In summary, HIF-1α is highly expressed in the late stages of PKD and is associated with an increase in LC3-II and beclin-1. The first demonstration of autophagosomes in PKD kidneys is reported. Inhibition of HIF-1α did not have a therapeutic effect.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 2-Methoxyestradiol
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy*
  • Beclin-1
  • Blotting, Western
  • Disease Models, Animal
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Fluorescent Antibody Technique
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Kidney / drug effects
  • Kidney / metabolism*
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Microtubule-Associated Proteins / metabolism
  • Polycystic Kidney Diseases / genetics
  • Polycystic Kidney Diseases / metabolism*
  • Polycystic Kidney Diseases / pathology
  • Rats
  • TRPP Cation Channels / deficiency
  • TRPP Cation Channels / genetics


  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • Becn1 protein, rat
  • Hif1a protein, mouse
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • LC3 protein, rat
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • TRPP Cation Channels
  • polycystic kidney disease 2 protein
  • Estradiol
  • 2-Methoxyestradiol