Tubuloglomerular feedback and salt-sensitive hypertension

描述(申请人提供)：高血压影响超过25%的成年人，是我们人口的主要心血管风险。超过一半的高血压患者对盐敏感，当盐的摄入量改变时，他们的血压会有显著的波动。然而，盐敏感的机制尚不清楚。肾小球滤过率(GFR)的增加在钠摄入量引起的急性容量扩张后迅速消除钠的过程中起着至关重要的作用，从而有助于恢复钠和水的平衡，从而维持正常的血压。这种GFR反应在人类和盐敏感型高血压动物模型中是钝化的。肾小管球蛋白反馈是肾小球滤过率的重要调节因子。增加肾小管血流量，通过增加向致密斑区(MD)输送的氯化钠，启动转化生长因子反应，从而触发信号，增强传入小动脉的张力，从而降低GFR。肾小球滤过率的下降有助于将MD流量恢复到正常水平，并防止氯化钠排泄的显著变化。然而，在持续的情况下，如实验性或餐后容量扩张，内在机制重置转化生长因子，从而将操作点转移到更高的流速，从而允许GFR上升。重置转化生长因子可促进 盐和水的排泄机制可能依赖于抑制血管紧张素II和增加一氧化氮(NO)系统的活性。来自MD的NO已被证明扩张传入小动脉和钝化转化生长因子。这种NO主要由神经元型一氧化氮合酶(NNOS)产生，在MD中大量表达。然而，MD传递的NO和转化生长因子在调节容量动态平衡中的作用仅是这些实验的假设。我们仍然不知道MD和TGF的NO是否在控制盐-水平衡和血压方面发挥作用，这是本提案的重点。在这个方案中，我们将检验MD中的nNOS�是一种盐敏感亚型的假设，它有助于MD在高盐摄入时增加NO的产生。增强的一氧化氮合酶�活性可钝化转化生长因子并增加肾小球滤过率，这是快速消除盐负荷和恢复盐水平衡所必需的机制。MD产生的NO不足会导致盐敏感型高血压。

DESCRIPTION (provided by applicant): Hypertension affects over 25% of the adults and is a major cardiovascular risk to our population. More than half of hypertensive humans are salt-sensitive and have significant blood pressure fluctuations when salt intake is altered. However, the mechanisms for salt-sensitivity are not clear. Increases in glomerular filtration rate (GFR) play a vital role in the rapid elimination of sodium following acute volume expansion associated with ingestion of a sodium load, thereby contributing to restoration of sodium and water balance which maintains normal blood pressure. This GFR response is blunted in humans and in animal models with salt-sensitive hypertension. Tubuloglomerular feedback (TGF) is an essential regulator of GFR. Increasing tubular flow initiates a TGF response mediated by raising NaCl delivery to the macula densa (MD), which triggers signals that enhance the tone of the afferent arterioles and thereby reduces GFR. This fall in GFR helps restore MD flow rate toward normal and prevents marked changes in NaCl excretion. However, in persistent situations such as experimental or postprandial volume expansion, intrinsic mechanisms reset TGF, which shifts the operating point to a higher flow rate thus allowing GFR to rise. TGF resetting could facilitate the excretion of salt and water via mechanisms that may be dependent on suppression of angiotensin II and increased activity of the nitric oxide (NO) system. NO derived from the MD has been shown to dilate the afferent arteriole and blunt TGF. This NO is mainly produced by neuronal NO synthase (nNOS), which is abundantly expressed in the MD. However, the roles of the MD-delivered NO and TGF in regulation of volume homeostasis are only assumptions from these experiments. We still do not know whether NO from the MD and TGF play any roles in control of salt-water balance and blood pressure, which is the focus of this proposal. In this proposal, we will test the hypothesis that nNOS� in the MD is a salt sensitive isoform, which contributes to enhanced NO generation by the MD during high salt intake. Enhanced nNOS� activity blunts TGF and increases GFR, a mechanism which is essential in rapid elimination of a salt load and restoration of salt-water balance. Inadequate NO generation by the MD induces salt sensitive hypertension.