Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease
Proteinuria, inflammation, chronic hypoxia, and rarefaction of peritubular capillaries contribute to the progression of renal disease by affecting proximal tubular epithelial cells (PTECs). To study the transcriptional response that separates patients with a stable course from those with a progressive course of disease, we isolated PTECs by laser capture microdissection from cryocut tissue sections of patients with proteinuric glomerulopathies (stable n=20, progressive n=11) with a median clinical follow-up of 26 months. Gene-expression profiling and a systems biology analysis identified activation of intracellular vascular endothelial growth factor (VEGF) signaling and hypoxia response pathways in progressive patients, which was associated with upregulation of hypoxia-inducible-factor (HIF)-1alpha and several HIF target genes, such as transferrin, transferrin-receptor, p21, and VEGF-receptor 1, but downregulation of VEGF-A. The inverse expression levels of HIF-1alpha and VEGF-A were significantly superior in predicting clinical outcome as compared with proteinuria, renal function, and degree of tubular atrophy and interstitial fibrosis at the time of biopsy. Interactome analysis showed the association of attenuated VEGF-A expression with the downregulation of genes that usually stimulate VEGF-A expression, such as epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and HIF-2alpha. In vitro experiments confirmed the positive regulatory effect of EGF and IGF-1 on VEGF-A transcription in human proximal tubular cells. Thus, in progressive but not in stable proteinuric kidney disease, human PTECs show an attenuated VEGF-A expression despite an activation of intracellular hypoxia response and VEGF signaling pathways, which might be due to a reduced expression of positive coregulators, such as EGF and IGF-1.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2009 |
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| Erschienen: |
2009 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:89 |
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| Enthalten in: |
Laboratory investigation; a journal of technical methods and pathology - 89(2009), 3 vom: 15. März, Seite 337-46 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rudnicki, Michael [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.03.2009 Date Revised 16.02.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/labinvest.2008.158 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM185706614 |
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| 100 | 1 | |a Rudnicki, Michael |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease |
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| 500 | |a Date Revised 16.02.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Proteinuria, inflammation, chronic hypoxia, and rarefaction of peritubular capillaries contribute to the progression of renal disease by affecting proximal tubular epithelial cells (PTECs). To study the transcriptional response that separates patients with a stable course from those with a progressive course of disease, we isolated PTECs by laser capture microdissection from cryocut tissue sections of patients with proteinuric glomerulopathies (stable n=20, progressive n=11) with a median clinical follow-up of 26 months. Gene-expression profiling and a systems biology analysis identified activation of intracellular vascular endothelial growth factor (VEGF) signaling and hypoxia response pathways in progressive patients, which was associated with upregulation of hypoxia-inducible-factor (HIF)-1alpha and several HIF target genes, such as transferrin, transferrin-receptor, p21, and VEGF-receptor 1, but downregulation of VEGF-A. The inverse expression levels of HIF-1alpha and VEGF-A were significantly superior in predicting clinical outcome as compared with proteinuria, renal function, and degree of tubular atrophy and interstitial fibrosis at the time of biopsy. Interactome analysis showed the association of attenuated VEGF-A expression with the downregulation of genes that usually stimulate VEGF-A expression, such as epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and HIF-2alpha. In vitro experiments confirmed the positive regulatory effect of EGF and IGF-1 on VEGF-A transcription in human proximal tubular cells. Thus, in progressive but not in stable proteinuric kidney disease, human PTECs show an attenuated VEGF-A expression despite an activation of intracellular hypoxia response and VEGF signaling pathways, which might be due to a reduced expression of positive coregulators, such as EGF and IGF-1 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Perco, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Enrich, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Eder, Susanne |e verfasserin |4 aut | |
| 700 | 1 | |a Heininger, Dorothea |e verfasserin |4 aut | |
| 700 | 1 | |a Bernthaler, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Wiesinger, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Sarközi, Rita |e verfasserin |4 aut | |
| 700 | 1 | |a Noppert, Susie-Jane |e verfasserin |4 aut | |
| 700 | 1 | |a Schramek, Herbert |e verfasserin |4 aut | |
| 700 | 1 | |a Mayer, Bernd |e verfasserin |4 aut | |
| 700 | 1 | |a Oberbauer, Rainer |e verfasserin |4 aut | |
| 700 | 1 | |a Mayer, Gert |e verfasserin |4 aut | |
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