Angiotensin II regulates vascular endothelial growth factor via hypoxia-inducible factor-1alpha induction and redox mechanisms in the kidney.
Angiotensin II (AngII) is a cytokine that participates in renal damage. Vascular endothelial growth factor (VEGF) is constitutively expressed in the kidney and is involved in the progression of renal disease. The aim of this work was to investigate the relation between AngII and VEGF and the mechanisms involved in its regulation in the kidney. We have observed that in cultured tubuloepithelial cells (NRK52E cell line) AngII increased VEGF gene expression and promoter activation. Hypoxia-inducible factor-1 (HIF-1) is one of the main VEGF gene activators. AngII induces HIF-1alpha protein production and increases HIF-1 DNA-binding activity. An antisense HIF-1alpha oligodeoxynucleotide inhibited AngII-induced VEGF overexpression. The reactive oxygen species act as second messengers in kidney damage caused by AngII and mediate the induction of HIF-1 by cytokines. In tubuloepithelial cells, VEGF up-regulation and HIF-1alpha induction due to AngII were significantly diminished by antioxidants, suggesting a redox-mediated mechanism. Infusion of AngII into mice caused renal VEGF overexpression, HIF-1 activation, and oxidative stress. In summary, these data show that AngII in vivo and in vitro up-regulates renal VEGF expression by a mechanism that involves HIF-1 activation and oxidative stress.
Sánchez-López
Elsa
E
Laboratory of Vascular and Renal Pathology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
López
Andrés Felipe
AF
Esteban
Vanesa
V
Yagüe
Susana
S
Egido
Jesus
J
Ruiz-Ortega
Marta
M
Alvarez-Arroyo
M Victoria
MV
D000804:Angiotensin II / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D000975:Antioxidants; D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D004247:DNA