Tubuloglomerular Feedback Regulation by Carbon Monoxide

一氧化碳的肾小球反馈调节

• 批准号: 8376983
• 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: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376983
• 关键词: Accounting; Address; Adenosine; Anions; 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; 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; mRNA Expression; 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，使压力尿钠曲线向右移动。这 传入小动脉 (Af-Art) 是肾血管阻力的主要来源。它控制肾小球滤过率 肾功能。 Af-Art 阻力受到与控制其他小动脉类似的因素的调节。在 此外，Af-Art 受肾小球反馈 (TGF) 控制。 TGF 通过致密斑起作用， 它感知到腔内 NaCl 的增加并发送信号来收缩 Af-Art。肾脏表达 血红素加氧酶 (HO)，释放一氧化碳 (CO)、胆绿素和二价铁。我们有 有证据表明，H2O 抑制可增强 TGF，而 CO 和胆绿素可减弱 TGF。我们假设 HO 在 致密斑产生 CO 和胆绿素，两者协同作用并以自分泌方式 抑制TGF。 CO 通过抑制 Na-K-2CI 协同转运蛋白 (NKCC2) 和阻断 ATP 释放来发挥作用。 胆绿素通过减少超氧化物 (O2-) 发挥作用，从而增加一氧化氮的生物利用度。这个假设将是 测试了 4 个目标：目标 I。假设：致密斑中的 HO-2 释放 CO，从而抑制 自分泌方式。目标二。假设：CO 通过刺激 cGMP 产生来抑制 TGF。 cGMP 抑制 TGF 部分是通过激活 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 NKCC2 依赖性 Na 进入减少。目的 三．假设：CO 诱导的 cGMP 产生部分通过阻断去极化诱导的 Ca 来抑制 TGF 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，从而减少 O2-。 O2- 的减少增加了 NO 的生物利用度。通过这些 机制 胆绿素抑制 TGF 并增强 CO 的作用。我们将在体外和体内研究 TGF。 除了药理学探针外，HO-2、-1 或一氧化氮合酶 1 基因缺失的小鼠将被 用过的。该项目与中心主题相关，因为我们将研究自分泌因子（CO 和胆绿素） 由参与肾脏微循环调节的致密斑细胞产生，因此 对调节肾功能起关键作用。该项目的信息将与来自 所有其他项目。它将使用所有核心。 CO 调节 TGF 的假设是一个新的范式 将有助于更好地了解控制肾脏微循环和功能的机制。