Defective recovery and severe renal damage after acute hemolysis in hemopexin-deficient mice

Hemopexin (Hx) is a plasma glycoprotein mainly expressed in liver and, less abundantly, in the central and peripheral nervous systems. Hx has a high b inding affinity with heme and is considered to be a major transport vehicle of heme into the liver, thus preventing both heme-catalyzed oxidative dama ge and heme-bound iran loss. To determine the physiologic relevance of heme -Hx complex formation, Hx-deficient mice were generated by homologous recom bination in embryonic stem (ES) cells. The Hx-deficient mice were viable an d fertile. Their plasma iron level and blood parameters were comparable to those of control mice and they showed no evidence of tissue lesions caused by oxidative damage or abnormal iron deposits. Moreover, they were sensitiv e to acute hemolysis, as are wild-type mice, Nevertheless, Hx-null mice rec overed more slowly after hemolysis and were seen to have more severe renal damage than controls. After hemolytic stimulus, Hx-deficient mice presented prolonged hemoglobinuria with a higher kidney iron load and higher lipid p eroxidation than control mice. Moreover, Hx-null mice showed altered posthe molysis haptoglobin (Hp) turnover in as much as Hp persisted in the circula tion after hemolytic stimulus, These data indicate that, although Hx is not crucial either for iron metabolism or as a protection against oxidative st ress under physiologic conditions, it does play an important protective rol e after hemolytic processes. (C) 1999 by The American Society of Hematology .