title: Involvement of hypoxia-inducible transcription factors in polycystic kidney disease.
abstract: In polycystic kidney disease (PKD), erythropoietin (EPO) production and interstitial vascularization are increased compared with other kidney diseases. EPO and several angiogenic factors are controlled by hypoxia-inducible transcription factors (HIFs), which are composed of a constitutive beta-subunit and two alternative alpha-subunits (HIF-1alpha, HIF-2alpha). We hypothesized that cyst expansion may result in pericystic hypoxia and consecutive up-regulation of HIF and thus examined the expression of HIF-alpha and HIF target genes in human PKD and in a rodent PKD model. HIF-1alpha and HIF-2alpha were found to be up-regulated in cyst epithelium and cells of cyst walls, respectively. The distinct expression pattern of the HIF-alpha isoforms closely resembles the respective pattern in normal kidneys under systemic hypoxia. Pimonidazole staining, a marker for tissue hypoxia, confirmed the existence of regional hypoxia in polycystic kidneys. Immunohistochemistry for selected target genes implicated a role for HIF-1alpha in vascular endothelial growth factor and Glut-1 activation and HIF-2alpha in endoglin and EPO stimulation. Polycystin-deficient cells showed physiological, oxygen-dependent HIF-alpha modulation, excluding a direct influence of polycystin deficiency on HIF-alpha regulation. In conclusion, HIF accumulation in human and rat PKD seems to be responsible for increased EPO production and pericystic hypervascularity and may have an impact on progression of PKD.
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander-University, Krankenhausstrasse 12, D-91054 Erlangen, Germany. wanja.bernhardt@med4.imed.uni-erlangen.de
authors.forename: Wanja Michael
authors.initials: WM
authors.lastname: Bernhardt
authors.forename: Michael Sean
authors.initials: MS
authors.lastname: Wiesener
authors.forename: Alexander
authors.initials: A
authors.lastname: Weidemann
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitt
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.forename: Philipp
authors.initials: P
authors.lastname: Lechler
authors.forename: Valentina
authors.initials: V
authors.lastname: Campean
authors.forename: Albert Chee Meng
authors.initials: AC
authors.lastname: Ong
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D015687:Cell Hypoxia / Q000502:physiology*; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D007690:Polycystic Kidney Diseases / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D050396:TRPP Cation Channels / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D051272:Glucose Transporter Type 1; D051547:Heme Oxygenase-1; D050396:TRPP Cation Channels; D042461:Vascular Endothelial Growth Factor A; C496541:HMOX1 protein, human