OVEREXPRESSION OF HUMAN APOLIPOPROTEIN-A-I IN TRANSGENIC RATS AND THEHYPERLIPOPROTEINEMIA ASSOCIATED WITH EXPERIMENTAL NEPHROSIS

Hyperlipoproteinemia contributes both to kidney disease progression an d the development of atherosclerosis. Elevated high density lipoprotei n cholesterol and apolipoprotein A-I (apoA-I) serum levels are indepen dent factors protective against the atherosclerotic process. We examin ed the effects in a transgenic rat model of human apoA-I expression on the hyperlipoproteinemia and edema after puromycin aminonucleoside-in duced nephrosis in three groups of animals: low line (TgR[hAI](low), h uman plasma apoA-I = 16.0 mg/dl); high line (TgR[hAI](high), 284 mg/dl ); and non-transgenic litter mates (TgR[hAI](non)). Nephrosis increase d 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 incr ease was due mainly to elevations of serum human apoA-I. The hepatic s teady-state levels of rat apoA-I mRNA increased 5- to 7-fold in all th ree groups, while human apoA-I mRNA levels increased 21- and 65-fold i n the low and high expressing groups, respectively, indicating a diffe rent degree of responsiveness of the rat and human genes. While nephro tic TgR[hAI](non) and TgR[hAI](low) rats showed severe hyperlipoprotei nemia 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 sign ificantly increased in the TgR[hAI](high) group, indicating this as on e possible mechanism for the relatively lower serum levels of these li pids. We conclude that the human apoA-I gene is responsive to nephrosi s 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.