Regulation of renal Microcirulation

在高血压患者，肾血管阻力增加，使压力钠尿曲线右移。这个 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和 肾功能。房颤-ART抵抗的调节因素与控制其他小动脉的因素相似。在……里面 此外，Af-Art受肾小管球反馈(TGF)控制。转化生长因子通过致密黄斑起作用， 它感觉到腔内Naci的增加，并发出信号来收缩Af-Art。肾宣泄 血红素加氧酶(HOS)，释放一氧化碳(CO)、胆绿素和亚铁。我们有 有证据表明，HO抑制增强了转化生长因子，而一氧化碳和胆绿素则降低了转化生长因子。我们假设霍斯在 致密黄斑产生一氧化碳和胆绿素，两者协同作用并以自分泌的方式 抑制转化生长因子。CO通过抑制Na-K-2CI协同转运体(NKCC2)和阻止ATP释放发挥作用。 胆绿素通过减少超氧阴离子(O2-)，从而增加NO的生物利用度。这一假设将是 测试在4个目标：目标I.假设：HO-2在致密黄斑释放一氧化碳，这抑制了转化生长因子在一个 独裁的方式。目的II.假设：一氧化碳通过刺激cGMP的产生抑制转化生长因子。CGMP对转化生长因子的抑制作用 部分通过激活cGMP依赖的蛋白激酶和cGMP刺激的磷酸二酯酶2，从而 降低cAMP浓度。CAMP的减少导致NKCC2依赖的Na内流减少。目标 III.假设：协同诱导的cGMP产生抑制转化生长因子，部分是通过阻断去极化诱导的钙离子 进入和/或抑制最大阴离子通道活性和ATP释放。目的IV.假设：黄斑中存在HO-2 Densa释放胆绿素，从而降低O2-。O2-的减少增加了NO的生物利用度。通过这些 胆绿素抑制转化生长因子和增强一氧化碳作用的机制我们将在体外和体内对转化生长因子进行研究。 除了药物探针，HO-2，-1，或一氧化氮合酶1基因缺失的小鼠将被 使用。这个项目与中心主题有关，因为我们将研究自分泌因子(CO和胆绿素) 由参与调节肾脏微循环的致密斑细胞产生，因此 在调节肾功能方面起着关键作用。来自该项目的信息将与来自 所有其他项目。它将使用所有内核。一氧化碳调节转化生长因子的假说是一种新的范式和 将有助于更好地了解控制肾脏微循环和功能的机制。

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.