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(American Journal of Pathology. 2007;170:830-842.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060455

Involvement of Hypoxia-Inducible Transcription Factors in Polycystic Kidney Disease

Wanja Michael Bernhardt*, Michael Sean Wiesener*{dagger}, Alexander Weidemann*, Roland Schmitt{ddagger}, Wilko Weichert§, Philipp Lechler*{dagger}, Valentina Campean, Albert Chee Meng Ong||, Carsten Willam*, Norbert Gretz** and Kai-Uwe Eckardt*

From the Department of Nephrology and Hypertension,* the Interdisciplinary Center for Clinical Research,{dagger} Nikolaus-Fiebiger-Center for Molecular Medicine, and the Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; the Department of Nephrology,{ddagger} Franz Volhard Clinic, Berlin, Germany; the Institute of Pathology,§ Charité-University Medicine, Berlin, Germany; the Medical Research Centre,** Klinikum Mannheim, University of Heidelberg, Mannheim, Germany; and the Academic Nephrology Unit,|| Sheffield Kidney Institute, Division of Clinical Sciences (North), University of Sheffield, Sheffield, United Kingdom

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 ß-subunit and two alternative {alpha}-subunits (HIF-1{alpha}, HIF-2{alpha}). 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-1{alpha} and HIF-2{alpha} 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-1{alpha} in vascular endothelial growth factor and Glut-1 activation and HIF-2{alpha} 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.




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