Tubuloglomerular feedback and salt-sensitive hypertension

描述（由申请人提供）：高血压影响超过25%的成年人，是我们人群的主要心血管风险。超过一半的高血压患者对盐敏感，当盐摄入量改变时，血压会出现显著波动。然而，盐敏感性的机制尚不清楚。肾小球滤过率（GFR）的增加在与摄入钠负荷相关的急性容量扩张后钠的快速消除中起着至关重要的作用，从而有助于恢复维持正常血压的钠和水平衡。这种GFR反应在人类和盐敏感性高血压动物模型中是迟钝的。 肾小管肾小球反馈（TGF）是GFR的重要调节因子。增加肾小管流量启动TGF应答，其通过提高向致密斑（MD）的NaCl递送来介导，这触发增强传入小动脉的张力的信号，从而降低GFR。GFR的下降有助于MD流速恢复正常，并防止NaCl排泄发生显著变化。然而，在持续的情况下，如实验或餐后容量扩张，内在机制重置TGF，这将工作点转移到更高的流速，从而使GFR上升。TGF重置可以促进 通过可能依赖于抑制血管紧张素II和增加一氧化氮（NO）系统活性的机制排泄盐和水。来自MD的NO已显示扩张传入小动脉和钝化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在调节体积稳态中的作用仅是来自这些实验的假设。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中起任何作用，这是本提案的焦点。 在这个建议中，我们将测试的假设，即nNOS在MD是一个盐敏感的亚型，这有助于增强NO生成的MD在高盐摄入量。增强的nNOS活性钝化TGF并增加GFR，这是一种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不足诱导盐敏感性高血压。

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.