Involvement of hypoxia-inducible transcription factors in polycystic kidney disease.
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.
Bernhardt
Wanja Michael
WM
Department of Nephrology and Hypertension, Friedrich-Alexander-University, Krankenhausstrasse 12, D-91054 Erlangen, Germany. wanja.bernhardt@med4.imed.uni-erlangen.de
Wiesener
Michael Sean
MS
Weidemann
Alexander
A
Schmitt
Roland
R
Weichert
Wilko
W
Lechler
Philipp
P
Campean
Valentina
V
Ong
Albert Chee Meng
AC
Willam
Carsten
C
Gretz
Norbert
N
Eckardt
Kai-Uwe
KU
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
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