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| Item Type: | Article |
|---|---|
| Title: | Involvement of hypoxia-inducible transcription factors in polycystic kidney disease |
| Creators Name: | Bernhardt, W.A., Wiesener, M.S., Weidemann, A., Schmitt, R., Weichert, W., Lechler, P., Champean, V., Ong, A.C.M., Willam, C., Gretz, N. and Eckhardt, K.U. |
| 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-{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-{alpha} and HIF-{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-{alpha} in vascular endothelial growth factor and Glut-1 activation and HIF-2α 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. |
| Keywords: | Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Erythropoietin, Gene Expression, Glucose Transporter Type 1, Heme Oxygenase-1, Immunoblotting, Immunohistochemistry, Polycystic Kidney Diseases, TRPP Cation Channels, Vascular Endothelial Growth Factor A, Animals, Rats |
| Source: | American Journal of Pathology |
| ISSN: | 0002-9440 |
| Publisher: | American Society for Investigative Pathology |
| Volume: | 170 |
| Number: | 3 |
| Page Range: | 830-842 |
| Date: | March 2007 |
| Official Publication: | https://doi.org/10.2353/ajpath.2007.060455 |
| PubMed: | View item in PubMed |
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