Hypoxia is believed to play an important role in the pathogenesis of acute and chronic
kidney disease. However, the impact of low oxygen tensions on cellular functions in
the kidney and potential adaptive responses are poorly understood.
In order to assess the effects of regional hypoxia, we induced large segmental renal
infarcts in rats by renal artery branch ligation to create an oxygen gradient vertical
to the corticomedullary axis and studied the effects on cell morphology, the induction
of hypoxia-inducible transcription factors (HIF), the expression of HIF target genes,
and cell proliferation.
Pimonidazol protein adduct immunohistochemistry, a marker for severe tissue hypoxia,
verified a continuous area of hypoxic renal tissue extending from the cortex to the
papilla, in which tubular necrosis developed subsequently. Within this area local
sparing of pimonidazol staining and tissue preservation was found around arcuate veins,
indicating regional oxygen supply via diffusion from venous blood. HIF-1alpha was
up-regulated within 1 hour and for up to 7 days predominantly in the border zone of
the infarct in tubular cells, glomerular cells, resident interstitial cells, capillary
endothelial cells, and infiltrating macrophages. HIF-2alpha expression was less prominent
and confined to resident and infiltrating peritubular cells in the cortex. HIF expression
was colocalized with regional up-regulation of the hypoxia-inducible genes heme oxygenase-1
and vascular endothelial growth factor (VEGF), and was followed by capillary and tubular
proliferation.
Our findings illustrate a marked potential of renal tissue to respond to regional
ischemia and initiate adaptive reactions, including angiogenesis.