Tubuloglomerular feedback and salt-sensitive hypertension

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。更 超过一半的高血压患者是盐敏感的，当盐浓度升高时， 摄入量发生了变化。然而，盐敏感性的机制尚不清楚。肾小球滤过增加 GFR在急性容量扩张后钠的快速消除中起着至关重要的作用， 摄入钠负荷，从而有助于恢复钠和水平衡， 血压正常。这种GFR反应在人类和具有盐敏感性的动物模型中是钝化的。 高血压 肾小管肾小球反馈（TGF）是GFR的重要调节因子。增加小管流量启动TGF 通过增加向致密斑（MD）的NaCl递送介导的反应，其触发增强 紧张的传入小动脉，从而降低GFR。GFR的下降有助于恢复MD流速， 正常和防止显着变化的氯化钠排泄。然而，在持续的情况下， 实验性或餐后容量扩张，内在机制重置TGF，这改变了操作 指向更高的流速，从而允许GFR升高。TGF-β重置可促进盐的排泄， 水通过机制，可能依赖于抑制血管紧张素II和增加的活性， 一氧化氮（NO）系统。来自MD的NO已被证明扩张传入小动脉并使其变钝。 的tgf这种NO主要由神经元型NO合酶（nNOS）产生，其在MD中大量表达。 然而，MD递送的NO和TGF在调节体积内稳态中的作用仅是 这些实验的假设。我们仍然不知道来自MD的NO和TGF是否在 控制盐-水平衡和血压，这是本建议的重点。 在这个提议中，我们将检验MD中的nNOS是盐敏感亚型的假设， 有助于在高盐摄入期间MD产生的NO增加。增强的nNOS活性钝化 TGF和增加GFR，这是一种在快速消除盐负荷和恢复正常代谢中必不可少的机制。 盐水平衡MD产生的NO不足诱导盐敏感性高血压。

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.