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 apoESendai may also directly influence renal and arterial homeostasis. We investigated the effects of macrophage-expressed apoESendai in apoE(-/-) mice with or without LDL receptor (LDLR). Murine bone marrow transduced to express apoE2, apoE3, or apoESendai was transplanted into lethally irradiated mice. Macrophage apoESendai expression 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 apoESendai and apoE3 in apoE(-/-) recipients. Macrophage apoESendai expression 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 apoESendai protects against atherosclerosis while causing lipoprotein glomerulopathy. This is the first demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.
Highlights
F apoESendai may directly influence renal and arterial homeostasis
Human apoE is present on most serum lipoproteins and plays a protective role in atherosclerosis by acting both as a ligand for receptor-mediated lipoprotein clearance and as an acceptor for cholesterol exported by peripheral cells [1, 2]. apoE on triglyceride-rich lipoproteins binds to the LDL receptor (LDLR), the LDLR-related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs) [3, 4]
About 90% of serum apoE is made in the liver [10] and the remainder is produced by macrophages [11]. apoE made by macrophages is secreted into the circulation, where it associates with lipoproteins and mediates their hepatic uptake by the liver [3, 6]
Summary
F apoESendai may directly influence renal and arterial homeostasis. We investigated the effects of macrophageexpressed apoESendai in apoE؊/؊ mice with or without LDL receptor (LDLR). Macrophage apoESendai expression 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 apoESendai and apoE3 in apoE؊/؊ recipients. Macrophage apoESendai expression 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. Macrophage expression of apoESendai protects against atherosclerosis while causing lipoprotein glomerulopathy. This is the first demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.—Tavori, H., D. Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice.
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