Virus-mediated Transduction of Apolipoprotein E (ApoE)-Sendai Develops Lipoprotein Glomerulopathy in ApoE-deficient Mice

Yasushi Ishigaki,Shinichi Oikawa,Takashi Suzuki,Shinichi Usui,Kenta Magoori,Dong-Ho Kim,Hiroyuki Suzuki,Jun Sasaki,Hironobu Sasano,Mitsuyo Okazaki,Takayoshi Toyota,Takao Saito,Tokuo T Yamamoto

doi:10.1074/jbc.m005906200

Abstract

Lipoprotein glomerulopathy (LPG) is a unique renal disease characterized by thrombus-like substances in markedly dilated glomerular capillaries, dysbetalipoproteinemia, and elevated plasma concentrations of apoE. Recent studies identified several apoE mutations in patients with LPG, including apoE2(R145P) Sendai (apoE-Sendai). Virus-mediated transduction of apoE-Sendai in apoE-deficient hypercholesterolemic mice resulted in insufficient correction of hypercholesterolemia and a marked and temporal induction of plasma triglyceride levels. In vitro binding studies showed that apoE-Sendai has a reduced affinity for the low density lipoprotein receptor, suggesting that dysbetalipoproteinemia in LPG is caused by the apoE mutation. Furthermore, histological examination revealed marked intraglomerular depositions of apoE-containing lipoproteins in mice injected with apoE-Sendai virus. These LPG-like depositions were detected 6 days after virus injection and were sustained for at least 60 days. Our results demonstrated that apoE-Sendai is an etiological cause of LPG.

Highlights

Genetic abnormalities in lipoprotein metabolism are associated with various disorders ranging from classical familial hypercholesterolemia to renal diseases including lipoprotein glomerulopathy (LPG).1 LPG is a recently identified renal disease originally described in 1989 by Saito et al [1]
We have provided direct evidence that apoESendai as an etiological cause of LPG using adenovirus-mediated gene transfer in apoE-deficient mice
The data presented in this study strongly suggest that dysbetalipoproteinemia manifested by severe hypercholesterolemia and hypertriglyceridemia in patients with LPG is caused by the apoE-Sendai mutation

Summary

Introduction

Genetic abnormalities in lipoprotein metabolism are associated with various disorders ranging from classical familial hypercholesterolemia to renal diseases including lipoprotein glomerulopathy (LPG). LPG is a recently identified renal disease originally described in 1989 by Saito et al [1]. LPG is a recently identified renal disease originally described in 1989 by Saito et al [1] It is characterized by intraglomerular lipoprotein thrombi associated with dysbetalipoproteinemia and proteinuria and is frequently manifested in nephrotic syndrome and renal failure. Excluding apoE-Kyoto, all these mutations occurred within exon 4 of the human apoE gene, which contains a cluster of basic amino acids constituting a site responsible for binding to the low density lipoprotein (LDL) receptor [9]. These amino acid mutations may account for dysbetalipoproteinemia in patients with LPG, whether they are related to abnormal lipoprotein deposition in LPG remained unclarified. We provide the first evidence that apoE-Sendai is an etiological cause of LPG

Methods

Results

Conclusion