Kraus, Andre and Peters, Dorien J. M. and Klanke, Bernd and Weidemann, Alexander and Willam, Carsten and Schley, Gunnar and Kunzelmann, Karl and Eckardt, Kai-Uwe and Buchholz, Bjoern (2018) HIF-1 alpha promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease. KIDNEY INTERNATIONAL, 94 (5). pp. 887-899. ISSN 0085-2538, 1523-1755
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Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations of the PKD1 gene and characterized by growth of bilateral renal cysts. Cyst growth is accompanied by regional hypoxia and induction of hypoxia-inducible factor (HIF)-1 alpha in cyst-lining epithelial cells. To determine the relevance of HIF-1 alpha for cyst growth in vivo we used an inducible kidney epithelium-specific knockout mouse to delete Pkd1 at postnatal day 20 or 35 to induce polycystic kidney disease of different severity and analyzed the effects of Hif-1 alpha co-deletion and HIF-1 alpha stabilization using a prolyl-hydroxylase inhibitor. HIF-1 alpha expression was enhanced in kidneys with progressive cyst growth induced by early Pkd1 deletion, but unchanged in the milder phenotype induced by later Pkd1 deletion. Hif-1 alpha co-deletion significantly attenuated cyst growth in the severe, but not in the mild, phenotype. Application of a prolyl-hydroxylase inhibitor resulted in severe aggravation of the mild phenotype with rapid loss of renal function. HIF-1 alpha expression was associated with induction of genes that mediate calcium-activated chloride secretion. Thus, HIF-1 alpha does not seem to play a role in early cyst formation, but accelerates cyst growth during progressive polycystic kidney disease. This novel mechanism of cyst growth may qualify as a therapeutic target.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; PROLYL HYDROXYLASE INHIBITORS; ACTIVATED CHLORIDE SECRETION; FORMING EPITHELIAL-CELLS; TRANSCRIPTION FACTORS; INJURY; ANEMIA; GROWTH; ERYTHROPOIETIN; PROLIFERATION; hypoxia; hypoxia-inducible factor-1 alpha; polycystic kidney disease; prolyl-hydroxylase inhibitors |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 Oct 2019 10:15 |
| Last Modified: | 10 Oct 2019 10:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13646 |
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