Angiostatin and matrix metalloprotease expression following ischemic acute renal failure.
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 lysine-Sepharose 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 postrecovery (8-35 days postischemia). 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 vascular endothelial cell growth factor-induced proliferation of human aortic endothelial cells in vitro; an effect that was blocked by coincubation 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 postischemic kidney. Matrix metalloproteinase (MMP)-2 and MMP-9, which may mediate angiostatin generation, were enhanced in postischemic kidney tissue and were localized to the renal tubules, interstitial cells, and the tubulo-interstitial space. These data indicate the possible local synthesis of angiostatin following acute renal failure (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.
Basile
David P
DP
Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA. dbasile@mcw.edu
Fredrich
Katherine
K
Weihrauch
Dorothee
D
Hattan
Naoichiro
N
Chilian
William M
WM
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000503:physiopathology; D000345:Affinity Labels; D043168:Angiostatins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000906:Antibodies; D005109:Extracellular Matrix / Q000201:enzymology; D015870:Gene Expression; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000201:enzymology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012685:Sepharose / Q000031:analogs & derivatives*
D000345:Affinity Labels; D000906:Antibodies; D012333:RNA, Messenger; C030675:lysine-sepharose; D043168:Angiostatins; D010958:Plasminogen; D012685:Sepharose; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9