title: Aristolochic acid I and ochratoxin A differentially regulate VEGF expression in porcine kidney epithelial cells--the involvement of SP-1 and HIFs transcription factors.
abstract: 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 NFκB 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-2α but not HIF-1α 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.
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Stachurska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kozakowska
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Loboda
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D007668:Kidney / Q000187:drug effects*; D018374:LLC-PK1 Cells; D009793:Ochratoxins / Q000633:toxicity*; D016329:Sp1 Transcription Factor / Q000502:physiology*; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D034341:Aristolochic Acids; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009793:Ochratoxins; D016329:Sp1 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C025589:ochratoxin A; C000228:aristolochic acid I