RENAL PROTEOGLYCANS--EFFECTS OF DIABETES AND HYPERTROPHY

肾蛋白聚糖——糖尿病和肥大的影响

• 批准号: 3239882
• 负责人: ELIAS MEEZAN
• 金额: $ 15.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 1991-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3239882
• 关键词: basement membrane; diabetic nephropathy; drug related diabetes mellitus; growth /development; heparan sulfate; hormone regulation /control mechanism; insulin; insulinlike factor; kidney hypertrophy; laboratory rat; proteoglycan; renal glomerulus; renal tubule; streptozotocin

The overall objective of this proposal is to investigate the effects of growth and hormonal controls on proteoglycan synthesis in isolated rat renal glomeruli and tubules. Proteoglycans have recently been identified as key components of the basement membrane layer of the glomeruli and tubules. Heparan sulfate is the predominant proteoglycan in the basement membrane and has been implicated to have a critical role in the maintenance of the selective permeability function of the glomerulus, where it serves as an anionic charge barrier to plasma proteins. This permeability barrier is compromised in diabetes mellitus and certain nephrotic syndromes and this alteration is a primary pathological consequence of these conditions. Renal hypertrophy is an early consequence of the diabetic state in animals and humans and may be the initiating factor in the resulting renal pathology, but virtually nothing is known about the effects of growth, and insulin and insulin-like growth factors (IGF's) on renal proteoglycan synthesis. We have recently demonstrated the presence of receptors for insulin and IGF's in glomeruli and tubules and the known anabolic effects of these hormones and particularly the implication of the IGF's as sulfation factors point to their possible involvement in the control of proteoglycan synthesis in the kidney. We are therefore proposing to compare the types and amounts of proteoglycans synthesized in vitro by renal glomeruli and tubules and to dissect the growth effects from the hormonal controls involved in this process. Two animals models will be used: (1) the uninephrectomized rat in which the remnant kidney undergoes a rapid hypertrophy and (2) the streptozotocin-diabetic rat in which early hypertrophy occurs in the absence of circulating insulin. Isolated glomeruli and tubles from normal, diabetic ard uninephrectomized animals will be incubated with 35SO4=, 3H-glucosamine and 3H-galactose with or without insulin and IGF's and the labeled proteoglycans from the cell cytoplasm, cell membrane, basement membrane and incubation medium will be isolated and characterized to define the biosynthetic process in these tissues under different growth and hormonal stimuli. Possible controls on proteoglycan synthesis such as substrate availability, protein and carbohydrate phosphorylation and level of transferase activities will also be examined. It is anticipated that these studies will provide a metabolic basis for the control of renal proteoglycan biosynthesis in growth and disease states.

本提案的总体目标是调查 蛋白多糖合成的生长和激素控制 离体大鼠肾小球和肾小管。 蛋白聚糖具有 最近被确定为地下室的关键组成部分 肾小球和肾小管的膜层。 硫酸乙酰肝素是 基底膜中的主要蛋白多糖， 被牵连到有一个关键作用，在维护的 肾小球的选择性渗透功能，在那里它服务 作为血浆蛋白的阴离子电荷屏障。 该渗透性 糖尿病和某些肾病患者的屏障受损 综合征，这种改变是一种原发性病理改变， 这些条件的后果。 肾肥大是一种早期 动物和人类糖尿病状态的后果， 是导致肾脏病理学的起始因素，但 事实上，我们对生长和胰岛素的影响一无所知， 和胰岛素样生长因子（IGF's）对肾蛋白多糖 合成. 我们最近证明了 胰岛素和胰岛素样生长因子的受体在肾小球和肾小管和 这些激素的已知合成代谢作用，特别是 IGF作为硫酸化因子的含义指出它们可能 参与蛋白多糖合成的控制， 肾 因此，我们建议比较这些类型， 肾小球体外合成蛋白多糖的量 和小管，并剖析激素对生长的影响， 在这个过程中涉及的控制。 两个动物模型将被 使用：（1）单侧肾切除大鼠，其中残肾 经历快速肥大和（2）链脲佐菌素糖尿病 在缺乏的情况下发生早期肥大的大鼠 循环胰岛素 分离肾小球和肾小管， 糖尿病和单侧肾切除的动物将与 35 SO 4 =，3 H-葡萄糖胺和3 H-半乳糖，伴或不伴胰岛素 IGF和来自细胞质的标记蛋白聚糖， 细胞膜、基底膜和孵育介质将 分离和表征，以确定生物合成过程， 这些组织在不同的生长和激素刺激下。 对蛋白聚糖合成的可能控制，如底物 可用性、蛋白质和碳水化合物磷酸化以及 还将检查转移酶活性。 预计各国 这些研究将为控制 生长和疾病状态下的肾蛋白聚糖生物合成。