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Modulation of renin secretion by renal cortical interstitial calcium

肾皮质间质钙调节肾素分泌

基本信息

批准号：
8525393
负责人：
Doug Atchison
金额：
$ 4.6万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-22 至 2014-08-21
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Our long-term objective is to elucidate the mechanisms of renin secretion. Increased extracellular calcium (Ca2+) decreases renin release in vitro by increasing juxtaglomerular (JG) cell intracellular Ca2+ and inhibiting adenylyl cyclase V (AC-V). How extracellular Ca2+ decreases rennin secretion in vivo and what initiates these changes in Ca2+ is unknown. Our hypothesis is that increased distal NaCI delivery increases Ca2+ in the renal cortical interstitium via paracellin-1 which stimulates the calcium-sensing receptor (CaR), inhibiting AC-V activity, leading to a decrease in renin secretion. AIM 1: Hypothesis: Increasing thick ascending limb NaCI transport increases cortical interstitial [Ca2+] via paracellin-1 and decreases renin secretion. We will measure changes in renal cortical interstitial Ca2+ using in situ microdialysis and changes in the renin secretory rate (RSR) in response to changes in NaCI delivery. We will measure interstitial Ca2+ and RSR after decreasing the expression of paracellin-1, a tight-junction protein responsible for paracellular Ca2+ reabsorption in the thick ascending limb, using RNA interference. We will measure changes in interstitial Ca2+ and RSR in response to the blockade of thick ascending limb NaCI reabsorption with furosemide. AIM 2: Hypothesis: In vivo stimulation of the CaR via cortical interstitial [Ca2+] decreases renin secretion. We will measure RSR while using calcimimetics to sensitize or the CaR in rats. We will measure changes in RSR to CaR activation in the presence of decreased interstitial [Ca2+] due to paracellin-1 knockdown. We will measure changes in RSR to CaR desensitization with calcilytics. We will measure RSR in the presence of increased interstitial [Ca2+] and CaR desensitization with calcilytics. AIM 3: Hypothesis: In vivo AC-V inhibition decreases renin secretion in the presence of decreased cortical interstitial [Ca2+]. We will measure basal RSR in response to the AC-V specific inhibitor NKY80. We will knockdown paracellin-1 expression in rats using siRNA technology and will measure interstitial [Ca2+] and RSR in the presence of the AC-V specific inhibitor, NKY80. We will knockdown AC-V expression in vivo using RNA interference, and measure interstitial [Ca2+] and RSR in response to furosemide. The renin-angiotensin system (RAS) is involved in almost every form of hypertension. Inhibition of the RAS is a mainstay of anti-hypertensive therapy. Understanding the function and regulation of the RAS will allow for the development of novel therapeutics to lessen the impact of high blood pressure.

描述（由申请人提供）：我们的长期目标是阐明肾素分泌的机制。细胞外Ca ~（2+）增加可通过增加肾小球（JG）细胞内Ca ~（2+）和抑制腺苷酸环化酶V（AC-V）来降低体外肾素释放。细胞外Ca 2+如何降低体内凝乳酶分泌以及是什么引发了Ca 2+的这些变化尚不清楚。我们的假设是，增加的远端NaCl递送通过副胞素-1增加肾皮质中的Ca 2+，副胞素-1刺激钙敏感受体（CaR），抑制AC-V活性，导致肾素分泌减少。目标1：假设：增加厚的上升肢体NaCl运输增加皮质间质[Ca 2 +]通过paracellin-1和降低肾素分泌。我们将使用原位微透析测量肾皮质间质Ca 2+的变化，以及响应NaCl递送变化的肾素分泌速率（RSR）的变化。我们将使用RNA干扰降低paracellin-1的表达后测量间质Ca 2+和RSR，paracellin-1是一种紧密连接蛋白，负责粗升支中的细胞旁Ca 2+重吸收。我们将测量间质Ca 2+和RSR的变化，以响应呋塞米对厚的上行肢体NaCl重吸收的阻断。目的2：假设：在体内通过皮质间质[Ca ~（2+）]刺激CaR减少肾素分泌。我们将测量RSR，同时使用拟钙剂致敏或大鼠的CaR。我们将测量由于paracellin-1敲低而导致的间质[Ca 2 +]减少的情况下RSR到CaR激活的变化。我们将测量RSR的变化，以CaR脱敏与calcilytics。我们将在间质[Ca 2 +]增加和CaR脱敏与calcilytics的存在下测量RSR。目的3：假设：在体内AC-V抑制减少皮质间质[Ca 2 +]减少的情况下的肾素分泌。我们将测量基础RSR对AC-V特异性抑制剂NKY 80的反应。我们将使用siRNA技术敲低大鼠中的paracellin-1表达，并将在AC-V特异性抑制剂NKY 80存在下测量间质[Ca 2 +]和RSR。我们将使用RNA干扰在体内敲低AC-V表达，并测量对呋塞米的反应的间质[Ca 2 +]和RSR。肾素-血管紧张素系统（RAS）参与几乎所有形式的高血压。 RAS的抑制是抗高血压治疗的支柱。了解RAS的功能和调节将允许开发新的治疗方法来减轻高血压的影响。