Macrophage-derived apoESendaisuppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice

Abstract

Lipoprotein glomerulopathy (LPG) is a renal disease often accompanied by dyslipidemia and increased serum apoE levels. apoESendai(Arg145Pro), a rare mutant based on the apoE3 sequence carrying an apoE2 charge, causes LPG in humans and transgenic mice, but its effects on the artery wall are unknown. Macrophage expression of apoESendaimay also directly influence renal and arterial homeostasis. We investigated the effects of macrophage-expressed apoESendaiin apoE-/-mice with or without LDL receptor (LDLR). Murine bone marrow transduced to express apoE2, apoE3, or apoESendaiwas transplanted into lethally irradiated mice. Macrophage apoESendaiexpression reduced aortic lesion size and inflammation by 32 and 28%, respectively, compared with apoE2 in apoE-/-recipients. No differences in lesion size or inflammation were found between apoESendaiand apoE3 in apoE-/-recipients. Macrophage apoESendaiexpression also reduced aortic lesion size by 18% and inflammation by 29% compared with apoE2 in apoE-/-/LDLR-/-recipients. Glomerular lesions compatible with LPG with increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis were only observed in apoE-/-/LDLR-/-mice expressing apoESendai. Thus, macrophage expression of apoESendaiprotects against atherosclerosis while causing lipoprotein glomerulopathy. This is the first demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.