title: Overexpression of human apolipoprotein A-I in transgenic rats and the hyperlipoproteinemia associated with experimental nephrosis.
abstract: Hyperlipoproteinemia contributes both to kidney disease progression and the development of atherosclerosis. Elevated high density lipoprotein cholesterol and apolipoprotein A-I (apoA-I) serum levels are independent factors protective against the atherosclerotic process. We examined the effects in a transgenic rat model of human apoA-I expression on the hyperlipoproteinemia and edema after puromycin aminonucleoside-induced nephrosis in three groups of animals: low line (TgR[hAI]low, human plasma apoA-I = 16.0 mg/dl); high line (TgR[hAI]high, 284 mg/dl); and non-transgenic litter mates (TgR[hAI]non). Nephrosis increased total plasma apoA-I levels 2-fold in TgR[hAI]non rats (75 vs. 162 mg/dl) and 4-fold in the TgR[hAI]low (97 vs. 458 mg/dl) and TgR[hAI]high rats (356 vs. 1,346 mg/dl). In both transgenic lines, this increase was due mainly to elevations of serum human apoA-I. The hepatic steady-state levels of rat apoA-I mRNA increased 5- to 7-fold in all three groups, while human apoA-I mRNA levels increased 21- and 65-fold in the low and high expressing groups, respectively, indicating a different degree of responsiveness of the rat and human genes. While nephrotic TgR[hAI]non and TgR[hAI]low rats showed severe hyperlipoproteinemia and edema, much lower levels of edema and of serum triglycerides, phospholipids, and cholesterol were seen in the TgR[hAI]high group. Urinary excretion of apoA-I, phospholipids, and cholesterol was significantly increased in the TgR[hAI]high group, indicating this as one possible mechanism for the relatively lower serum levels of these lipids. We conclude that the human apoA-I gene is responsive to nephrosis and that human apoA-I-transgenic rats with this syndrome provide an animal model for the study of human high density lipoprotein and apoA-I metabolism.
authors.affiliation: Department of Metabolic Diseases, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
authors.forename: B F
authors.initials: BF
authors.lastname: Burkey
authors.forename: D
authors.initials: D
authors.lastname: France
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Ma
authors.forename: B
authors.initials: B
authors.lastname: Brand
authors.forename: C
authors.initials: C
authors.lastname: Abuhani
authors.forename: M R
authors.initials: MR
authors.lastname: Diffenderfer
authors.forename: J B
authors.initials: JB
authors.lastname: Marsh
authors.forename: J R
authors.initials: JR
authors.lastname: Paterniti
authors.forename: E A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D002784:Cholesterol / Q000097:blood / Q000652:urine; D004487:Edema / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006951:Hyperlipoproteinemias / Q000097:blood / Q000139:chemically induced / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D009401:Nephrosis / Q000097:blood* / Q000139:chemically induced / Q000652:urine; D010743:Phospholipids / Q000097:blood / Q000652:urine; D011692:Puromycin Aminonucleoside; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D010743:Phospholipids; D012333:RNA, Messenger; D012709:Serum Albumin; D014280:Triglycerides; D011692:Puromycin Aminonucleoside; D002784:Cholesterol