Abstract 479: Expression of ApoE-sendai by Macrophages Causes Lipoprotein Glomerulopathy While Suppressing Atherosclerosis
Renal disease is usually associated with lipoprotein abnormalities. Lipoprotein glomerulopathy (LPG) is a unique disease characterized by intraglomerular lipoprotein thrombi, often in the absence of dyslipidemia. Macrophages are not involved in lipid accumulation in LPG. ApoESendai is an apoE variant known to cause LPG in heterozygous carriers. It carries the same charge as the apoE2 common variant, but is due to a proline-for-arginine substitution at position 145 in the apoE3 sequence. The effects of macrophage expression of apoESendai on LPG and atherosclerosis have not been studied.We have characterized renal and arterial responses in apoE-/- or apoE-/-/LDLR-/- (DKO) mice expressing apoESendai exclusively in macrophages. Bone marrow from apoE-/- mice was transduced with lentiviral constructs expressing either human apoE2 or apoESendai, and then transplanted into apoE-/- or DKO recipient mice.Compared to BMT controls, both apoESendai and apoE2 macrophages significantly decreased plasma cholesterol levels in apoE-/- recipients (22.6% and 19.4%, respectively). No changes in serum cholesterol levels were found in DKO recipients compared to controls. Macrophage expression of apoESendai and apoE2 was associated with plasma human apoE levels of 6.9±1.9 and 5.4±1.7 μg/ml, respectively, in apoE-/- recipients, and 18.9±2.8 and 18.4±3.8 μg/ml, respectively, in DKO recipients. All mice displayed extensive kidney tubular lesions, which correlated with the severity of dyslipidemia. While none of the apoE-/- recipients showed any additional kidney damage, DKO mice expressing apoESendai showed clear features of LPG, with lesions in the glomerular capillaries characterized by mesangial cell expansion. Macrophage apoE2 expression by apoE-/- BMT recipients reduced aortic lesion size by 22.7% compare to BMT controls (p<0.01). Surprisingly, macrophage apoESendai expression further reduced aortic lesion size by 27.6% compared to apoE2 expression in apoE-/- mice (p<0.01). A similar 26.1% reduction was seen in DKO recipients transplanted with apoESendai compared to apoE2 expressing macrophages.Our results show for the first time that macrophage expression of apoESendai protects against atherosclerosis while causing glomerular disease.
- © 2013 by American Heart Association, Inc.