Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice

Abstract Background: Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant kidney disease that is most commonly caused by mutations in ApoE Kyoto (p.R43C) and ApoE Sendai (p.R163P). Differences in phenotype among the various ApoE mutations have been suggested, but the pathogenic role of ApoE Kyoto has not been validated in an animal model. This study intended to establish an ApoE Kyoto murine model and to further compare the pathologic differences between ApoE Kyoto and ApoE Sendai.Methods: Male ApoE-deficient mice, 3 months of age, were divided into five groups, including the Ad-ApoE Sendai, Ad-ApoE Kyoto, Ad-ApoE3, Ad-eGFP, and ApoE (−/−) groups. The first four groups received recombinant adenovirus that contained the entire coding regions of the human ApoE Sendai and ApoE Kyoto, apoE3, and eGFP genes, respectively. Fasting blood and urine samples were collected at multiple time points. Lipid profiles and urine albumin–creatinine ratio were measured. Renal and aortic histopathologic alterations were analyzed.Results: After virus injection, plasma human ApoE was detected and rapidly reached the maximum level at 4–6 days in the Ad-ApoE Kyoto and Ad-ApoE Sendai groups (17.4 ± 3.1 µg/mL vs.: 22.2 ± 4.5 µg/mL, respectively) and at 2 days in the Ad-apoE3 group (38.4 µg/mL). The serum total cholesterol decreased by 63%, 65%, and 73% in the Ad-ApoE Kyoto, Ad-ApoE Sendai, and Ad-apoE3 groups, respectively. There were no significant changes in serum triglyceride and urinary albumin–creatinine ratio among the five groups. Typical lipoprotein thrombi with positive ApoE staining were detected in the ApoE Kyoto and ApoE Sendai groups. The Oil-red O-positive glomerular area tended to be higher in the Ad-ApoE Kyoto group (9.2%) than in the Ad-ApoE Sendai (3.9%), Ad-apoE3 (4.8%), Ad-eGFP (2.9%), and ApoE (−/−) (3.6%) groups. The atherosclerotic plaque area in the aorta was lower in the group injected with various ApoE mutations than in the group without injection of ApoE mutation.Conclusions: In this animal study, we first established an ApoE Kyoto mutation murine model and confirmed its pathogenic role in LPG. Our results suggested that LPG may be more severe with the ApoE Kyoto than with the ApoE Sendai.