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expression follows microvascular loss in advanced murine Adriamycin nephrosis
1 Renal Medicine, The University of Sydney at Westmead Millennium Institute, Sydney, NSW, Australia
2 Institute of Veterinary Physiology, The University of Zurich, Zurich, Switzerland
* To whom correspondence should be addressed. E-mail: lukask{at}med.usyd.edu.au.
Background and methods 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 hypoxiainducible factor-1 (HIF-1
) in animals 7, 14 and 28 days after Adriamycin. Results were assessed in conjunction with quantitation of the cortical micro-vasculature (by CD34 immunostaining) and cortical
expression of vascular endothelial growth factor (VEGF). Cortical apoptosis was also examined by TUNEL staining. Results A dramatic and significant increase in nuclear localization of HIF-1 was seen 28 days
after Adriamycin in the context of severe glomerular and tubulointerstitial damage. Areas of nuclear HIF-
1 staining did not co-localize with areas of cellular apoptosis. AN was also associated with a significant attenuation of the peri-tubular capillaries that was significant at 14 and 28 days after adriamycin. Cortical VEGF expression fell in a step-wise manner from day 7 until day 28 after Adriamycin. Conclusions 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 (ie 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.
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