Apolipoprotein E-related glomerular disorders

Abstract Of the glomerular disorders that occur due to apolipoprotein E (apoE) mutations, apoE2 homozygote glomerulopathy and lipoprotein glomerulopathy (LPG) have been identified. ApoE2 homozygote glomerulopathy was found in individuals expressing homozygous apoE2/2. This was characterized histologically by glomerulosclerosis with marked infiltration of foam cells derived from macrophages and, occasionally, with non-lamellated lipoprotein thrombi. Recently, several cases of apoE Toyonaka (Ser197Cys) combined with homozygous apoE2/2 have been reported, where non-immune membranous nephropathy-like features observed in glomeruli. Interestingly, in these cases, apoE accumulation was identified by tandem mass spectrometry. Therefore, it is speculated that these findings may arise from apoE molecules without lipids, which result from hinge damage by apoE Toyonaka and may cross the glomerular basement membrane as small molecules. LPG is primarily associated with heterozygous apoE mutations surrounding the LDL-receptor binding site , and it is histologically characterized by lamellated lipoprotein thrombi that lack foam cells. Recent studies have suggested that LPG can be induced by thermodynamic destabilization, hydrophobic surface exposure and the aggregation of apoE resulting from the incompatibility of apoE mutated residues within helical regions. Additionally, apoE5 may play a supporting role in the development of LPG and in lipid-induced kidney diseases via hyperlipoproteinemia. Thus, it is interesting that many apoE mutations contribute to characteristic glomerular disorders through various mechanisms. In particular, macrophages may uptake lipoproteins into the cytoplasm and contribute to the development of apoE2 homozygote glomerulopathy as foam cells, and their dysfunction may participate in the accumulation of lipoproteins in the glomerulus causing lipoprotein thrombi in LPG.(250words)