Journal
TOXICOLOGY LETTERS
Volume 204, Issue 2-3, Pages 118-126Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2011.04.022
Keywords
Nephropathy; Kidney diseases; Vascular endothelial growth factor; Angiogenesis; Hypoxia; LLC-PK1
Categories
Funding
- Polish Ministry for Science and Higher Education [N N401 297835, N N301 033440, POIG.02.01.00-12 064/08, POIG 01.01.02-00-109/09, POIG.02.02.00-014/08, 01.01.02-00-069/09]
- European Union
- Wellcome Trust
- Ministry of Science and Higher Education
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Aristolochic acid I (AAI) and ochratoxin A (OTA) cause chronic kidney diseases. Recently, the contribution of hypoxic injuries and angiogenic disturbances to nephropathies has been suggested, but underlying mechanisms have not been fully clarified yet. In porcine kidney epithelial cell line, LLC-PK1 cells, treatment with non-toxic doses of AAI increased whereas with OTA decreased production of vascular endothelial growth factor (VEGF), the angiogenic factor with well-defined functions in kidney. Moreover, the activity of transcription factors regulating VEGF expression was differentially affected by examined compounds. Activity of hypoxia inducible factors (HIFs) and SP-1 was increased by AAI but diminished by OTA. Interestingly, AP-1 activity was inhibited while NF kappa B was not influenced by both toxins. Mithramycin A, a SP-1 inhibitor, as well as chetomin, an inhibitor of HIFs, reversed AAI-induced up-regulation of VEGF synthesis, indicating the importance of SP-1 and HIFs in this effect. Additionally, adenoviral overexpression of HIF-2 alpha but not HIF-1 alpha prevented OTA-diminished VEGF production suggesting the protective effect of this isoform towards the consequences exerted by OTA. These observations provide new insight into complex impact of AAI and OTA on angiogenic gene regulation. Additionally, it adds to our understanding of hypoxia influence on nephropathies pathology. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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