EF6265, a Novel Plasma Carboxypeptidase B Inhibitor, Protects against Renal Dysfunction in Rat Thrombotic Glomerulonephritis through Enhancing Fibrinolysis

Abstract

Background/Aim: 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. Conclusion: EF6265, which inhibits plasma carboxypeptidase B, showed a protective effect on thrombotic renal dysfunction in thrombotic glomerulonephritis through enhancing the fibrinolysis.