Renal Control of Body Fluid Volume and Circulatory Dynamics

肾脏对体液量和循环动力学的控制

• 批准号: 7326800
• 负责人: Joey P. Granger
• 金额: $ 38.87万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7326800
• 关键词: Address; Affect; Angiotensin II; Angiotensins; Blood Vessels; Body Fluids; Cardiovascular system; Cessation of life; Chronic; Conscious; Cytokine Activation; Data; Defect; Disease; Elevation; Endothelial Cells; Endothelin; Endothelium; Estrogens; Event; Excretory function; Extracellular Fluid; Feedback; Functional disorder; Glomerular Filtration Rate; Grant; Hormonal; Hypertension; Hypertension induced by pregnancy; Kidney; Laboratories; Leukocytes; Mediating; Modeling; Morbidity - disease rate; Natriuresis; Oxidative Stress; Patient currently pregnant; Perfusion; Perinatal; Physiological; Placenta; Plasma; Play; Pregnancy; Progesterone; Proteinuria; Rattus; Reactive Oxygen Species; Receptor Activation; Receptor, Angiotensin, Type 1; Regulation; Renal Plasma Flow; Renal function; Research Personnel; Role; Sodium; System; Testing; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; blood pressure regulation; concept; cytokine; glomerular filtration; human TNF protein; instrument; neutrophil; pregnancy hypertension; pressure; programs; research study; response

The kidneys play a central role in long-term regulation of extracellular fluid volume and arterial pressure. A common defect that has been found in all forms of hypertension examined to date is a hypertensive shift in the pressure natriuresis relationship. During the previous project period, studies from our laboratories determined the physiological mechanisms whereby endothelial-derived factors and neurohormonal systems alter renal-pressure natriuresis and blood pressure regulation in a rat model of pregnancy-induced hypertension (PIH), produced by chronic reductions in uterine perfusion pressure. In this proposal, a major objective is to define the interaction between endothelin, oxidative stress and tumor necrosis factor in mediating the altered renal-pressure natriuresis and hypertension in response to chronic reductions in uterine perfusion pressure in pregnant rats. The central hypothesis to be tested in this proposal is that a reduction in uteroplacental perfusion pressure causes hypertension by reducing renal-pressure natriuresis. The reduction in pressure natriuresis occurs as a result of placental and or leukocyte-derived cytokines causing endothelial cell activation that leads to enhanced formation of reactive oxygen species via endothelin, angiotensin II and cytokine-dependent mechanisms. These abnormalities reduce renal plasma flow and glomerular filtration thereby decreasing renal sodium excretory function. To test this hypothesis, arterial pressure, renal, hormonal, and endothelial function will be examined in a conscious, chronically-instrumented rat model of chronic PIH produced by long-term reductions in uterine perfusion pressure (RUPP). Data obtained in this model during the previous grant period indicate that the hypertension produced by decreased perfusion pressure to the uteroplacental unit is associated with proteinuria, significant reductions in renal plasma flow and GFR, a hypertensive shift in the pressure natriuresis relationship, cytokine activation, and endothelial dysfunction. Specific aims to be addressed are: 1) To test the hypothesis that abnormalities in cardiovascular and renal function during chronic reductions in uteroplacental perfusion pressure are due to elevations in maternal plasma TNF alpha 2) To test the hypothesis that endothelin plays an important role in mediating TNF alpha-induced abnormalities in cardiovascular and renal function in pregnant rats 3) To test the hypothesis that estrogens and or progesterone enhance the endothelial activation and hypertensive response to TNF alpha 4) To test the hypothesis that reactive oxygen species mediate abnormalities in cardiovascular and renal function during chronic reductions in uteroplacental perfusion pressure.

肾脏在细胞外液量和动脉压的长期调节中发挥核心作用。迄今为止，在所有形式的高血压检查中发现的一个常见缺陷是血压尿钠排泄关系的高血压转变。在上一个项目期间，我们实验室的研究确定了内皮源性因子和神经激素系统改变妊娠高血压（PIH）大鼠模型肾压尿钠排泄和血压调节的生理机制， 由子宫灌注压长期降低引起。在这个建议中，一个主要的目标是确定内皮素，氧化应激和肿瘤坏死因子之间的相互作用，介导的改变肾压尿钠排泄和高血压，以应对慢性降低子宫灌注压在怀孕的大鼠。本研究的中心假设是子宫胎盘灌注压降低通过减少肾压尿钠排泄引起高血压。压力性尿钠排泄的减少是一种 胎盘和/或白细胞衍生的细胞因子引起内皮细胞活化的结果，通过内皮素、血管紧张素II和精氨酸依赖性机制导致活性氧的形成增强。这些异常减少肾血浆流量和肾小球滤过，从而降低肾钠排泄功能。为了验证这一假设，将在一个清醒的、慢性仪器化的慢性妊高征大鼠模型中检查动脉压、肾、激素和内皮功能，该模型是通过长期减少子宫内膜异位症而产生的。 灌注压（RUPP）。在此模型中获得的数据表明，在以前的授权期间，子宫胎盘单位的灌注压降低所产生的高血压与蛋白尿，肾血浆流量和GFR的显着减少，高血压的压力尿钠排泄关系的转变，细胞因子激活，内皮功能障碍。具体目标如下：1）检验子宫胎盘灌注压慢性降低期间心血管和肾功能异常是由于母体血浆TNF α升高所致的假设2）检验内皮素在介导TNF α诱导的妊娠大鼠心血管和肾功能异常中起重要作用的假设3）为了检验雌激素和/或孕酮增强内皮活化和对TNF α的高血压反应的假设，为了检验在子宫胎盘灌注压慢性降低期间活性氧介导心血管和肾功能异常的假设。