INCREASED SUSCEPTIBILITY IN HP KNOCKOUT MICE DURING ACUTE HEMOLYSIS

Haptoglobin, a conserved plasma glycoprotein, forms very stable solubl e complexes with free plasma hemoglobin. Hemoglobin binding by haptogl obin is thought to be important in the rapid hepatic clearance of hemo globin from the plasma and in the inhibition of glomerular filtration of hemoglobin. To evaluate these functions, Haptoglobin knockout (-/-) mice were created. These mice were viable but had a small, significan t reduction in postnatal viability. Contrary to popular belief, the la ck of haptoglobin did not impair clearance of free plasma hemoglobin i n -/- mice. Induction of severe hemolysis by phenylhydrazine caused ex tensive hemoglobin precipitation in the renal tubular cells of both -/ - and +/+ mice, with death occurring in 55% of -/- mice and in 18% of +/+ mice. In general, phenylhydrazine-treated -/- mice suffered greate r tissue damage, as evidenced by the induction of hepatic acute phase response resulting in increased plasma alpha 1-acid glycoprotein (AGP) levels. Among -/- and +/+ mice that survived, -/- mice tend to suffer greater oxidative damage and failed to repair or regenerate damaged r enal tissues, as indicated by their higher plasma malonaldehyde (MDA) and 4-hydroxy-2(E)-nonenal (HNE) levels and lower mitotic indices in t heir kidneys, respectively. This study Suggested that a physiologicall y important role;of hemoglobin-haptoglobin complex formation is the am elioration of tissue damages by hemoglobin-driven lipid peroxidation. (C) 1998 by The American Society of Hematology.