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Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Lipoprotein glomerulopathy induced by ApoE-Sendai is different from glomerular lesions in aged apoE-deficient mice
Atsunori Ishimura1, Maho Watanabe1, Hitoshi Nakashima2
1Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonann-ku, Fukuoka, 814-0180, Japan.
Objective:
A mutant of apolipoproteinE (apoE), ApoE-Sendai (Arg145Pro), is one of the major causative factors of human lipoprotein glomerulopathy (LPG). An apoE-deficient mouse with introduced ApoE-Sendai gene (ApoE-Sendai mouse) developed a murine counterpart of LPG, whereas it was also reported that apoE-deficient mouse (apoE KO mouse) spontaneously developed LPG-like lesion regardless of introduction of ApoE-Sendai gene. In the present study, we differentiated renal lesions between these two models by detailed analyses of histology and lipoprotein profile, and clarified the role of apoE variants.
Method:
ApoE-Sendai mice were induced by injection of adenovirus vectors. The kidneys showing LPG-like lesions in apoE-Sendai and apoE KO mice were histopathologically evaluated. Plasma lipids and lipoproteins of both mice were also examined.
Results:
Histological alteration of the kidney in ApoE-Sendai mice was observed with light microscopy (in 40 out of 50 mice; mild 24, moderate 13, severe 3). Characteristic lesions were dilated vascular lumens mimicking lipoprotein thrombi in human LPG. Similar changes were found in hematoxylin-eosin stained sections of aged apoE KO mice. Meanwhile, periodic acid-Schiff, Azan Mallory, and Oil red O/Sudan III stained sections revealed that the dilated lumens of ApoE-Sendai mice mainly contained lipids and lipoproteins but those of aged apoE KO mice contained much other materials, e.g., proteins and fibrils. These findings were supported by electron micrographs, in which round-shaped droplets indicating lipoproteins were observed in ApoE-Sendai mice but not in aged apoE KO mice. In the kidney of apoE KO mice many anti-mouse CD68 Ab positive cells were detected. This contrasts with the result seen in ApoE-Sendai mice. The plasma lipoprotein compositions of the two types of mice were totally different.
Conclusion:
It was certain that the kidneys of aged apoE KO mice showed morphological alteration, but the histological findings of glomerular lesions were different from those seen in the kidneys of ApoE-Sendai mice. According to the histological findings and plasma lipoprotein profile, ApoE-Sendai mice, not apoE KO mice, is a murine model for human LPG. This means that apoE variants are essential to LPG.
Insights
ApoE-Sendai mice, not apoE knockout mice, accurately model human lipoprotein glomerulopathy (LPG). This highlights the essential role of apolipoprotein E (apoE) variants in developing LPG, differentiating it from spontaneous kidney lesions in apoE-deficient models.
Area of Science:
- Nephrology
- Genetics
- Biochemistry
Background:
- Human lipoprotein glomerulopathy (LPG) is linked to apolipoprotein E (apoE) mutations, specifically ApoE-Sendai (Arg145Pro).
- ApoE-deficient (apoE KO) mice spontaneously develop LPG-like kidney lesions, complicating the study of apoE variants in LPG pathogenesis.
Purpose of the Study:
- To differentiate renal lesions between ApoE-Sendai and apoE KO mice.
- To clarify the specific role of apoE variants in the development of LPG.
Main Methods:
- Induction of ApoE-Sendai mice using adenovirus vectors.
- Histopathological evaluation of kidney lesions in ApoE-Sendai and apoE KO mice.
- Analysis of plasma lipid and lipoprotein profiles in both mouse models.
Main Results:
- ApoE-Sendai mice exhibited kidney lesions with dilated lumens containing lipids and lipoproteins, mimicking human LPG.
- Aged apoE KO mice showed similar morphological alterations but with different contents (proteins, fibrils) and inflammatory cell infiltration.
- Distinct plasma lipoprotein compositions were observed between ApoE-Sendai and apoE KO mice.
Conclusions:
- Kidney lesions in aged apoE KO mice differ histologically from those in ApoE-Sendai mice.
- ApoE-Sendai mice serve as a valid murine model for human LPG, unlike apoE KO mice.
- Apolipoprotein E variants are critical for the development of LPG.
