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1 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Anaesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
3 Department of Physiology, Louisiana State University Health Science Center, New Orleans, LA, USA
* To whom correspondence should be addressed. E-mail: dbasile{at}mcw.edu.
Ischemic injury to the kidney results in blood vessel loss and predisposition to chronic renal disease. Angiostatin is a proteolytic cleavage product of plasminogen that inhibits angiogenesis, promotes apoptosis of endothelial cells and disrupts capillary integrity. A combination of lysinesepharose enrichment followed by western blotting was used to study the expression of angiostatin in response to the induction of ischemic renal injury. No angiostatin products were readily detectable in kidneys of sham-operated control rats. In contrast, both 38 and 50 kDa forms of angiostatin were dramatically enhanced in the first 3 days following 45 min ischemia/reperfusion injury. Renal angiostatin levels declined, but remained detectable at late time-points post-recovery (8-35 days post-ischemia). Angiostatin-like immunoreactivity was also elevated in the plasma and in urine for up to 35 days following injury. Lysine-sepharose extracts of either kidney or urine inhibited VEGF induced proliferation of human aortic endothelial cells in vitro; an effect that was blocked by co-incubation with an angiostatin antibody. RT-PCR verified that mRNA of the parent protein, plasminogen, was produced in the liver, but it was not present in either sham-operated or post-ischemic kidney. MMP-2 and MMP-9, which may mediate angiostatin generation, were enhanced in post-ischemic kidney tissue and were localized to the renal tubules, interstitial cells, and the tubulointerstitial space. These data indicate the possible local synthesis of angiostatin following ARF and suggest a possible role for MMPs in this activity. Renal angiostatin generation following ARF may modulate renal capillary density postischemia and thereby influence chronic renal function.
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