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

Lipoprotein glomerulopathy (LPG) is a renal disease often accompanied by dyslipidemia and increased serum apoE levels. apoE_Sendai(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 apoE_Sendaimay also directly influence renal and arterial homeostasis. We investigated the effects of macrophage-expressed apoE_Sendaiin apoE^-/-mice with or without LDL receptor (LDLR). Murine bone marrow transduced to express apoE2, apoE3, or apoE_Sendaiwas transplanted into lethally irradiated mice. Macrophage apoE_Sendaiexpression 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 apoE_Sendaiand apoE3 in apoE^-/-recipients. Macrophage apoE_Sendaiexpression 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 apoE_Sendai. Thus, macrophage expression of apoE_Sendaiprotects against atherosclerosis while causing lipoprotein glomerulopathy. This is the first demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.