REGULATION OF GLOMERULAR AND PROXIMAL NEPHRON FUNCTION

这项肾脏生理学项目的长期目标是阐明 调节肾单位功能的肾内机制。这项研究建议 在本续篇中，应用程序将评估与以下内容相关的三个假设 1)小管球球反馈(TGF)信号在黄斑的传递 肾小球旁结构(JGA)内的Densa，2)起始和 转化生长因子信号通过肾小球系膜向肾小球系膜外的传递 3)转化生长因子与小动脉之间的协同作用。 肌源性自动调节机制。这些研究将被执行 直接在体外的肾小球前血管和致密黄斑区域， 血液灌流的延髓旁肾和培养的肾小球系膜细胞 大鼠肾。具体目标是： 1.我们将评估转化生长因子信号的运输耦合假说 通过微穿孔和电生理研究传输到 确定a)致密黄斑的跨上皮电位差 以及在转化生长因子响应期间；b)净水通量和电流 通过致密斑块；c)溶质是否扩散到 与皮质肾小管周围相比，JGA间质有限。 间质。 2.我们将确定细胞外离子浓度的局部变化 和/或渗透压，被认为是在转化生长因子反应期间产生的， 刺激培养的肾小球系膜细胞，如果胞浆钙反应 传播到邻近的细胞。 3.我们将确定晚期传入血管收缩是否会产生协同作用 上行血管节段的肌源性收缩 血管内压，以及这一机制对 近端传入动脉和小叶间动脉的自身调节反应。 转化生长因子肌源性自身调节机制是血管紧张素转换酶 肾功能，已知它们在许多情况下被重置或抑制 病理生理状态。这项基础研究的结果 机制将与一些严重和昂贵的肾脏相关 疾病，包括糖尿病肾病、慢性肾功能衰竭和 高血压。

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.