Progressive renal disease is caused by a process of fibrosis that relentlessly destroys normal renal architecture and function. The number of patients with end-stage renal disease continues to rise exponentially, at an annual cost to Medicare that now exceeds $12 billion. The goal of the proposed studies is to determine how abnormalities of lipoprotein metabolism, which are frequently present in patients with renal disease, contribute to the pathogenesis of renal fibrosis. The overall hypothesis to be tested is that macrophage scavenger receptors process low density lipoproteins that have been oxidatively modified within the kidney to initiate fibrosis-promoting events. It is further hypothesized that this pathway worsens fibrosis in the face of hypercholesterolemia.
Three Specific Aims are proposed. (1) To determine the effects of hypercholesterolemia on the severity of renal fibrosis and to delineate the pattern of renal scavenger receptor expression in murine models of renal fibrosis. (2) To investigate the role of the macrophage scavenger receptor class A type I/II (SR-AI/II) and scavenger receptor CD36 in renal fibrosis. (3) To elucidate intrarenal changes in pro-oxidant and anti-oxidant enzymes that could promote lipoprotein oxidation in murine models of renal disease associated with hyperlipidemia. These in vivo studies will be based on four murine models of renal disease. The functional significance of the two best characterized macrophage scavenger receptors, which are also known to participate in atherogenesis, (SR-AI/II and CD36), will be determined by comparing renal disease severity between wild-type animals and scavenger receptor-deficient animals. Bone marrow transplantation studies will be done to distinguish between the role of renal and macrophage scavenger receptors. Our long-term objective is to provide a scientific basis for the development and use of new therapies for patients with progressive renal disease. It is anticipated that the results of the proposed studies will prove that hypercholesterolemia, intra-renal oxidation of low density lipoproteins and scavenger receptor-dependent interactions with oxLDL represent an important pathogenetic pathway of progressive renal damage.
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