HIF-1alpha expression follows microvascular loss in advanced murine adriamycin nephrosis.
Cellular hypoxia has been proposed as a major factor in the pathogenesis of chronic renal injury, yet to date there has been no direct evidence to support its importance. Therefore, we examined cortical hypoxia in an animal model of chronic renal injury (murine adriamycin nephrosis; AN) by assessing nuclear localization of the oxygen-dependent alpha-subunit of hypoxia-inducible factor-1 (HIF-1alpha) in animals 7, 14, and 28 days after adriamycin. Results were assessed in conjunction with quantitation of the cortical microvasculature (by CD34 immunostaining) and cortical expression of VEGF. Cortical apoptosis was also examined by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. A dramatic and significant increase in nuclear localization of HIF-1alpha was seen 28 days after adriamycin in the context of severe glomerular and tubulointerstitial damage. Areas of nuclear HIF-1alpha staining did not colocalize with areas of cellular apoptosis. AN was also associated with a significant attenuation of the peritubular capillaries that was significant at 14 and 28 days after adriamycin. Cortical VEGF expression fell in a stepwise manner from day 7 until day 28 after adriamycin. In conclusion, these data are consistent with a significant increase in cellular hypoxia occurring in the advanced stages of murine AN. Increased cortical hypoxia was preceded by significant reductions in both the number of peritubular capillaries (i.e., oxygen supply) and the angiogenic cytokine VEGF. Apart from providing the first direct evidence for cellular hypoxia in a model of chronic renal disease, these results suggest that a primary dysregulation of angiogenesis may be the cause of increased hypoxia in this model.
Kairaitis
Lukas Karolis
LK
Department of Renal Medicine, Westmead Hospital, Westmead, NSW 2145, Australia. lukask@med.usyd.edu.au
Wang
Yiping
Y
Gassmann
Max
M
Tay
Yuet-Ching
YC
Harris
David Charles Hamlyn
DC
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004317:Doxorubicin; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007668:Kidney / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009401:Nephrosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D004268:DNA-Binding Proteins; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin