Burkey B F, France D, Wang H, Ma X, Brand B, Abuhani C, Diffenderfer M R, Marsh J B, Paterniti J R, Fisher E A
Department of Metabolic Diseases, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
J Lipid Res. 1995 Jul;36(7):1463-73.
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.
高脂蛋白血症既会促使肾脏疾病进展，也会导致动脉粥样硬化的发生。高密度脂蛋白胆固醇和载脂蛋白A-I（apoA-I）血清水平升高是预防动脉粥样硬化进程的独立保护因素。我们在三组动物中研究了人apoA-I表达的转基因大鼠模型对嘌呤霉素氨基核苷诱导的肾病后高脂蛋白血症和水肿的影响：低表达系（TgR[hAI]low，人血浆apoA-I = 16.0 mg/dl）；高表达系（TgR[hAI]high，284 mg/dl）；以及非转基因同窝仔鼠（TgR[hAI]non）。肾病使TgR[hAI]non大鼠的血浆总apoA-I水平升高2倍（75对162 mg/dl），使TgR[hAI]low大鼠（97对458 mg/dl）和TgR[hAI]high大鼠（356对1346 mg/dl）的血浆总apoA-I水平升高4倍。在两个转基因系中，这种升高主要是由于血清人apoA-I水平升高所致。在所有三组中，大鼠apoA-I mRNA的肝脏稳态水平均升高了5至7倍，而在低表达组和高表达组中，人apoA-I mRNA水平分别升高了21倍和65倍，这表明大鼠和人基因的反应程度不同。虽然患肾病的TgR[hAI]non和TgR[hAI]low大鼠表现出严重的高脂蛋白血症和水肿，但在TgR[hAI]high组中观察到的水肿以及血清甘油三酯、磷脂和胆固醇水平要低得多。TgR[hAI]high组中apoA-I、磷脂和胆固醇的尿排泄量显著增加，这表明这是这些脂质血清水平相对较低的一种可能机制。我们得出结论，人apoA-I基因对肾病有反应，患有这种综合征的人apoA-I转基因大鼠为研究人高密度脂蛋白和apoA-I代谢提供了一种动物模型。
