REGULATION OF GLOMERULAR AND PROXIMAL NEPHRON FUNCTION

肾小球和近端肾单位功能的调节

• 批准号: 3227838
• 负责人: Leon C Moore
• 金额: $ 14.52万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-12-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3227838
• 关键词: calcium metabolism; chronic renal failure; computer simulation; cytoplasm; diabetic nephropathy; diuresis; glomerular filtration; hamsters; hormone regulation /control mechanism; hypertension; intracellular transport; juxtaglomerular apparatus; mathematical model; micropuncture; renal tubular transport; renal tubule; sodium chloride; vasoconstriction

The long-term goal of this project in renal physiology is to elucidate the intrarenal mechanisms that regulate nephron function. The studies proposed in this continuation application will evaluate three hypotheses related to 1) tubuloglomerular feedback (TGF) signal transmission across the macula densa in the juxtaglomerular apparatus (JGA), 2) the initiation and propagation of the TGF signal across the extraglomerular mesangium to the afferent arteriole, and 3) synergistic interactions between TGF and myogenic autoregulatory mechanisms. These studies will be performed directly in preglomerular vessels and the macula densa region of in vitro, blood-perfused, juxtamedullary nephrons and cultured mesangial cells from rat kidney. The specific aims are: 1. We will evaluate the transport-coupling hypotheses of TGF signal transmission with micropuncture and electrophysiological studies to determine a) the transepithelial potential differences at the macula densa and during a TGF response; b) the net water flux and electrical current through the macula densa cell plaque; c) whether solute diffusion into the JGA interstitium is limited in comparison to the cortical peritubular interstitium. 2. We will determine if local changes in extracellular ion concentration and/or osmolarity, which are thought to be generated during a TGF response, stimulate cultured mesangial cells, ad if the cytosolic calcium response is propagated to neighboring cells. 3. We will determine if late afferent vasoconstriction induces synergistic myogenic contraction of upstream vascular segments via elevated intravascular pressure, and the impact of this mechanism on the autoregulatory responses of proximal afferent and interlobular arteries. The TGF myogenic autoregulatory mechanisms are important mediators of kidney function, and they are known to be reset or inhibited in a number of pathophysiological states. The results of this basic research into the mechanisms will be relevant to a number of serious and costly renal diseases, including diabetic nephropathy, chronic renal failure, and hypertension.

该项目在肾脏生理学方面的长期目标是阐明 调节肾单位功能的肾内机制。 提出的研究 在此延续应用程序中，将评估与以下相关的三个假设 1) 肾小球反馈（TGF）信号穿过黄斑传输 球旁装置 (JGA) 中的致密体，2) 的启动和 TGF 信号通过肾小球系膜传播至肾小球 传入小动脉，以及 3) TGF 和 肌源性自动调节机制。 这些研究将进行 直接在体外的肾小球前血管和致密斑区域， 血液灌注的近髓肾单位和培养的系膜细胞 大鼠肾。 具体目标是： 1. 我们将评估TGF信号的转运耦合假设 通过微穿刺和电生理学研究进行传输 确定 a) 致密斑处的跨上皮电位差 以及 TGF 反应期间； b) 净水通量和电流 通过致密斑细胞斑块； c) 溶质是否扩散到 与皮质管周相比，JGA 间质受到限制 间质。 2. 我们将确定细胞外离子浓度是否发生局部变化 和/或渗透压，被认为是在 TGF 反应期间产生的， 刺激培养的系膜细胞，如果胞质钙反应是 传播到邻近细胞。 3. 我们将确定晚期传入血管收缩是否会产生协同作用 通过升高上游血管段的肌源性收缩 血管内压力，以及该机制对血管内压力的影响 近端传入动脉和小叶间动脉的自动调节反应。 TGF 肌源性自动调节机制是重要的调节因子 肾功能，并且已知它们在许多情况下被重置或抑制 病理生理状态。 这项基础研究的成果 机制将与许多严重且昂贵的肾脏疾病有关 疾病，包括糖尿病肾病、慢性肾功能衰竭等 高血压。