Role of apolipoprotein E variants in lipoprotein glomerulopathy and other renal lipidoses

Abstract

Lipoprotein glomerulopathy (LPG) is a new renal lipidosis entity, characterized by peculiar histology and abnormal lipoprotein profiles mimicking type III hyperlipoproteinemia. Recently, it has been clarified that LPG is associated with novel apolipoprotein E (apoE) mutations. In particular, ApoE-Sendai, which substitutes arginine 145 with proline, is observed in most Japanese patients with LPG, although isoelectric focusing polyacrylamide gel electrophoresis has shown that it is consistent with the apoE2 isoform. To confirm the etiological role of these apoE mutations, we established an animal model of LPG. The model was created by the introduction of recombinant adenovirus containing human apoE-Sendai into apoE knockout mice. Both clinical and experimental findings indicate that LPG is caused not only by hyperlipoproteinemia but also by an in situ interaction between apoE variants and glomerular elements. In addition, several studies suggest that the apoE2 mutation is responsible for the development of diabetic nephropathy and IgA nephropathy, as well as renal lipidosis with type III hyperlipoproteinemia. In this review, we present the clinical and histological features of LPG and its pathogenesis, and discuss the role of apoE abnormalities, especially apoE-Sendai and apoE2, in LPG and other renal lipidoses.

Lipoprotein glomerulopathy induced by ApoE-Sendai is different from glomerular lesions in aged apoE-deficient mice

“…Some cases with specific renal lesions for LPG showed normal lipid profile [2,16]. Therefore, LPG is considered not to be caused by hyperlipoproteinemia due to reduced LDL receptor binding capacity by apoE variants, but to be caused by specific deposition of abnormal lipoproteins including apoE variants in the kidneys [10,17]. From this point of view, renal histology, especially electron microscopy [18] and lipid staining [19], is the most reliable diagnostic tool for LPG.…”

“…An apoE variant, Apo E2(Arg145Pro) Sendai, was initially identified [4], and subsequently several other variants were also discovered in LPG patients [5][6][7][8][9]. These evidences have indicated that abnormal apoE is responsible for LPG [2,10], and that the structural changes of the binding site with lowdensity lipoprotein (LDL) receptor, 140-150 residues of apoE, result in type III hyperlipoproteinemia [5,[11][12][13].…”

A novel apolipoprotein E mutation, ApoE Tsukuba (Arg 114 Cys), in lipoprotein glomerulopathy

“…Thus, it was suggested that the ApoE mutations, ApoE Sendai, ApoE Tokyo and ApoE1 resulted in inefficient receptor binding and increased lipid, lipoprotein and ApoE levels. In general, however, LPG has not been associated with the extra-renal manifestation of hyperlipoproteinaemia and hyperlipidaemia, such as arteriosclerosis and xanthoma [3]. In patients with LPG, the presence of lipoprotein thrombi in almost all glomeruli, the absence of foam cells and elevated ApoE level were typical features [2].…”

“…In previous studies, it has been reported that ApoE mutations, ApoE Sendai (Arg 145 Pro), ApoE Kyoto (Arg 25 Cys), ApoE Tokyo/Maebashi (3 amino acid deletion, residues 141 to 143) and ApoE1 (18 amino acid deletion, residues 156 to 173) are associated with LPG [3]. ApoE has a major role in the metabolism of lipids and lipoproteins.…”

“…In most of the LPG patients, levels of intermediate-density lipoproteins are elevated, resembling type III hyperlipoproteinaemia; moreover, apolipoprotein E (ApoE) levels are also elevated. Recent genetic studies have revealed that several ApoE gene mutations are associated with LPG [3].…”