EF6265, a novel plasma carboxypeptidase B inhibitor, protects against renal dysfunction in rat thrombotic glomerulonephritis through enhancing fibrinolysis.
OBJECTIVE
Plasma carboxypeptidase B is a physiological fibrinolysis inhibitor. In the present study, the effects of EF6265, a novel specific plasma carboxypeptidase B inhibitor, on renal dysfunction in a rat thrombotic glomerulonephritis model were examined.


METHODS
The model was induced by injection of anti-glomerular basement membrane serum and lipopolysaccharide to rats. Renal microthrombosis was histologically evaluated by phosphotungstic acid-hematoxylin staining for fibrin thrombi. Renal dysfunction was evaluated on the basis of plasma levels of blood urea nitrogen as well as renal edemas and urine volume.


RESULTS
The glomerular microthrombi observed in a positive control group were significantly reduced after a short-term treatment (4 h) with EF6265 at a dose which enhanced fibrinolysis. The elevation of blood urea nitrogen and renal edema formation decreased, and the reduction of the urine volume improved after a long-term treatment (21 h) with EF6265. In addition, EF6265 had a protective activity against multiple organ dysfunction, because it reduced plasma lactate dehydrogenase and alanine aminotransferase levels and mortality in this model.


CONCLUSIONS
EF6265, which inhibits plasma carboxypeptidase B, showed a protective effect on thrombotic renal dysfunction in thrombotic glomerulonephritis through enhancing the fibrinolysis.
Muto
Yuko
Y
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan. yuko_muto@meiji.co.jp
Suzuki
Kokichi
K
Iida
Hiroyuki
H
Ishii
Hidemi
H
D000596:Amino Acids / Q000008:administration & dosage*; D000818:Animals; D043424:Carboxypeptidase B / Q000037:antagonists & inhibitors* / Q000097:blood*; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005342:Fibrinolysis / Q000187:drug effects*; D005921:Glomerulonephritis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D010721:Phosphinic Acids / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013927:Thrombosis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology
C487111:7-amino-2-(((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methyl)heptanoic acid; D000596:Amino Acids; D010721:Phosphinic Acids; D043424:Carboxypeptidase B