title: Hypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD).
abstract: 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.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado at Denver and Health Sciences Center, Aurora, 80262, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Belibi
authors.forename: Iram
authors.initials: I
authors.lastname: Zafar
authors.forename: Kameswaran
authors.initials: K
authors.lastname: Ravichandran
authors.forename: Anamarija Bauer
authors.initials: AB
authors.lastname: Segvic
authors.forename: Alkesh
authors.initials: A
authors.lastname: Jani
authors.forename: Danica Galesic
authors.initials: DG
authors.lastname: Ljubanovic
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D015153:Blotting, Western; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D050396:TRPP Cation Channels / Q000172:deficiency / Q000235:genetics
chemical_list: D000077584:2-Methoxyestradiol; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D004958:Estradiol; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008869:Microtubule-Associated Proteins; D050396:TRPP Cation Channels; C115010:Becn1 protein, mouse; C512829:Becn1 protein, rat; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; C526109:Anxa3 protein, rat; C480860:Map1lc3b protein, mouse