Mesangial expansion is a key feature in the pathogenesis of numerous renal diseases involving the glomerulus. Dyslipidemia is commonly associated with glomerulosclerosis; however, studies indicate that mutations in apolipoprotein E (apoE) might independently contribute to kidney dysfunction. Although the role of apoE as an atheroprotective molecule is well established, its role in kidney is unclear. In this study, we sought to explore if apoE has a protective function in kidney. Northern blotting and RT-PCR showed apoE expression in kidney; and mesangial cell is a major source of apoE in kidney. In the kidneys of 14-16 month old apoE null mice, hematoxylin-eosin staining revealed increased mesangial cell proliferation and matrix formation compared to wild type mice or apoB-overexpressing mice, which have elevated plasma lipoproteins. These data suggest that lack of apoE, rather than hyperlipidemia contributes to increased mesangial expansion. We isolated mesangial cells from mouse kidney and determined the effect of apoE on cell growth. ApoE (10 µg/ml) completely inhibited serum, PDGF (10ng/ml) as well as LDL induced mesangial cell proliferation. ApoE did not show any cytotoxic effect, and moreover inhibited mesangial cell apoptosis induced by oxidized LDL. These data suggest that apoE regulates growth as well as survival of mesangial cells. We previously showed that apoE induces heparan sulfate proteoglycan (HSPG), perlecan in vascular cells, which has an antiproliferative effect. Similarly, apoE induced the amount of mesangial cell HSPG both in the medium and in cells by 30% and 100% respectively. Immunohistochemistry revealed reduced staining of perlecan in kidney from apoE-null mice. Since loss of anionic HSPG is associated with disruption of filtration barrier, these data suggest a novel role for kidney apoE in preserving the filtration barrier. In summary apoE has a protective function in kidney as an autocrine regulator of mesangial expansion and kidney function.