Regulation of renal Microcirulation

肾脏微循环的调节

• 批准号: 7595340
• 负责人: Oscar A. Carretero
• 金额: $ 36.87万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595340
• 关键词: Accounting; Address; Adenosine; Anions; Arts; Biliverdine; Biological Availability; Caliber; Carbon Monoxide; Cell membrane; Cells; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diffuse; Dose; Feedback; Gases; Genes; Glomerular Filtration Rate; Heme; Hemin; Hypertension; In Vitro; Ionophores; Iron; Kidney; Lead; Macula densa; Measures; Membrane Potentials; Mesoporphyrins; Messenger RNA; Microcirculation; Mus; Natriuresis; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Oxygenases; Oxyhemoglobin; Perfusion; Play; Regulation; Renal function; Resistance; Role; Signal Transduction; Soluble Guanylate Cyclase; Superoxides; Techniques; Testing; Tubular formation; Vascular resistance; analog; arteriole; autocrine; basolateral membrane; blood pressure regulation; cGMP production; heme a; heme oxygenase-1; heme oxygenase-2; in vivo; inhibitor/antagonist; kidney vascular structure; novel; phosphoric diester hydrolase; pressure; prevent; protein expression; response; sodium-potassium chloride cotransporter 2 protein

In hypertension, renal vascular resistance increases, shifting the pressure natriuresis curve to the right. The afferent arteriole (Af-Art) accounts for most renal vascular resistance. It controls glomerular filtration rate and renal function. Af-Art resistance is regulated by factors similar to those that control other arterioles. In addition, the Af-Art is controlled by tubuloglomerular feedback (TGF). TGF operates via the macula densa, which senses increases in luminal NaCI and sends a signal to constrict the Af-Art. The kidney expresses heme oxygenases (HOs), which release carbon monoxide (CO), biliverdin, and ferrous iron. We have evidence that HO inhibition potentiates TGF, while CO and biliverdin reduce it. We hypothesize that HOs in the macula densa produce CO and biliverdin, both of which act synergistically and in an autocrine manner to inhibit TGF. CO acts by inhibiting the Na-K-2CI cotransporter (NKCC2) and by blocking ATP release. Biliverdin acts by decreasing superoxide (O2-), thereby increasing NO bioavailability. This hypothesis will be tested in 4 aims: Aim I. Hypothesis: HO-2 in the macula densa releases CO, which inhibits TGF in an autocrine manner. Aim II. Hypothesis: CO inhibits TGF by stimulating cGMP production. cGMP inhibits TGF in part by activating cGMP-dependent protein kinase and cGMP-stimulated phosphodiesterase 2, thereby reducing cAMP concentration. A decrease in cAMP results in decreased NKCC2-dependent Na entry. Aim III. Hypothesis: CO-induced cGMP production inhibits TGF, in part, by blocking depolarization-induced Ca entry and/or inhibiting maxi-anion channel activity and ATP release. Aim IV. Hypothesis: HO-2 in the macula densa releases biliverdin, which decreases O2-. The decrease in O2- increases NO bioavailability. Via these mechanisms biliverdin inhibits TGF and potentiates the effects of CO. We will study TGF in vitro and in vivo. In addition to pharmacological probes, mice with HO-2, -1, or nitric oxide synthase 1gene deletion will be used. This project relates to the central theme because we will study autocrine factors (CO and biliverdin) produced by the macula densa cells that participate in the regulation of renal microcirculation, and as a result play a key role in regulating renal function. The information from this project will be integrated with that from all other projects. It will use all of the cores. The hypothesis that CO regulates TGF is a new paradigm and will lead to a better understanding of the mechanisms that control renal microcirculation and function.

在高血压中，肾血管阻力增加，使压力尿钠排泄曲线向右移动。的 输入小动脉（Af-Art）占大多数肾血管阻力。它控制肾小球滤过率， 肾功能Af-Art抵抗力受与控制其他小动脉的因素类似的因素调节。在 此外，Af-Art受肾小管肾小球反馈（TGF）控制。TGF通过致密斑起作用， 其感知腔NaCl的增加并发送信号以收缩Af-Art。 血红素加氧酶（HO），其释放一氧化碳（CO）、胆绿素和亚铁。我们有 证据表明HO抑制增强TGF，而CO和胆绿素减少它。 致密斑产生CO和胆绿素，两者协同作用并以自分泌方式起作用， 抑制TGF。CO通过抑制Na-K-2Cl协同转运蛋白（NKCC 2）和阻断ATP释放发挥作用。 胆绿素通过减少超氧化物（O2-），从而增加NO的生物利用度。这一假设将是 在4个目标中测试：目标I。假设：致密斑中的HO-2释放CO，其抑制TGF-β 1表达。 自分泌方式Aim II.假设：CO通过刺激cGMP的产生抑制TGF。cGMP抑制TGF 部分通过激活cGMP依赖性蛋白激酶和cGMP刺激的磷酸二酯酶2，从而 降低cAMP浓度。cAMP减少导致NKCC 2依赖性Na内流减少。目的 三.假设：CO诱导的cGMP产生抑制TGF，部分是通过阻断去极化诱导的Ca 进入和/或抑制最大阴离子通道活性和ATP释放。目标四。假设：黄斑中的HO-2 densa释放胆绿素，降低O2-。O2-的减少增加了NO的生物利用度。经由这些 机制胆绿素抑制TGF和加强CO的影响。我们将在体外和体内研究TGF。 除了药理学探针外，HO-2、HO-1或一氧化氮合酶1基因缺失的小鼠将被 采用这个项目涉及的中心主题，因为我们将研究自分泌因子（CO和胆绿素） 由参与肾微循环调节的致密斑细胞产生， 在调节肾功能中起关键作用。该项目的信息将与 所有其他项目。它将使用所有的核心。CO调节TGF的假说是一种新的范式， 将导致更好地了解控制肾脏微循环和功能的机制。