Role of the Kidney in Iron Balance

肾脏在铁平衡中的作用

• 批准号: 9247896
• 负责人: Katherine Xu
• 金额: $ 4.4万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247896
• 关键词: ATP phosphohydrolase; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Affect; Anemia; Apical; Appearance; Back; Binding; Biological Availability; Biology; Blood; Blood Circulation; Bone Marrow; Bowman' s space; Brain Hypoxia-Ischemia; Bypass; Cell membrane; Cells; Chelating Agents; Chemistry; Chronic; Complex; Data; Development; Distal; Duct (organ) structure; Duodenum; Energy Metabolism; Enterocytes; Environment; Equilibrium; Erythroblasts; Failure; Food; Genes; Genetic; Hand; Hemochromatosis; Hepatocyte; Hormones; Host Defense; Human; Impairment; Injury; Iron; Iron Chelating Agents; Iron Overload; Kidney; Knock-out; LCN2 gene; LDL-Receptor Related Protein 2; Limb structure; Liver; Location; LoxP-flanked allele; Lysosomes; Maps; Mediating; Membrane; Micronutrients; Modeling; Molecular; Mus; Nephrons; Oxidants; Oxygen; Pathway interactions; Pattern; Pharmacology; Phosphate Buffer; Physiology; Play; Polymers; Proteins; Public Health; Reactive Oxygen Species; Recycling; Reducing Agents; Research; Role; SLC11A2 gene; Series; Serum; Source; TFRC gene; Testing; Thick; TimeLine; Tissues; Tracer; Transferrin; Tubular formation; Urine; Vesicle; Water; Woman; cell injury; cell type; chelation; hepcidin; inorganic phosphate; intrinsic factor-cobalamin receptor; iron deficiency; macrophage; metal transporting protein 1; mutant; novel; nucleotide metabolism; nutrition; organ growth; oxidation; oxygen transport; protein transport; public health relevance; symporter; tool; trafficking; urinary

 DESCRIPTION (provided by applicant): The biology of iron transport is dictated by the chemistry of iron. Free iron is present around 10-10M in water at neutral pH (in an oxygenated solution) and around 10-19M in the presence of phosphate buffers, concentrations too low to support cellular viability. Consequently, from the moment iron is liberated from food sources, to its final distribution in the cell, iron must be "handed-off" from one chelator to another chelator Failure of chelation, which is tantamount to the presentation of iron to reducing or oxidizing agents, results in reactive chemistry, while appropriate chelation solubilizes and protects iron from changes in oxidation state. In the past decade, a series of iron chelators, carriers and transporters (both proteins and organic molecules) have been identified which affect the exchange of iron from the gut lumen to nearly every cell of the body, even at neutral pH, in the presence of oxygen. These proteins and organic molecules provide both short range transport (across cell membranes) and long range transport (through the circulation) to deliver adequate amounts of iron to target cells and recycle iron from damaged cells. Almost no iron is lost to the environment meaning that the steady state can be maintained with limited replacement (approximately 1mg per day in humans). This means the capture and trafficking pathways are efficient and export of iron to the environment is contained. Mechanisms that capture and recycle iron have been described and have been most importantly studied in duodenal enterocytes or macrophages. Yet, a number of proteins which carry iron are filtered into the nephron, and acute and chronic kidney injury is well known to result in the appearance of iron in the urine, resulting in catalytic iron mediated damage. To understand iron trafficking in the kidney requires an analysis of iron trafficking proteins in many cell types along the course of the nephron. I have identified both canonical and non-cannonical localizations of these proteins in the nephron and I propose to understand how they remove iron from the urinary space and transport it safely to the blood. My lab has the expertise and all of the standard tools required fr these studies, such as a series of floxed-iron transporter genes, novel Cre Drivers, and tracers loaded with iron, to detect the location of cellular and urinary iron when different transporters ae deleted. Our preliminary results suggest that both proximal and distal nephron mechanisms are at play to capture iron including entirely unexpected mechanisms of luminal iron traffic. The preliminary results also suggest that renal iron traffic may be under control of hepcidin, meaning that like the liver, duodenum, and macrophage, the kidney is engaged not only in local iron trafficking but is likely to be a contributor to systemic iron balance. Results from the proposed study will provide molecular implications for iron-mediated damage in acute kidney injury.

 描述（由申请人提供）：铁转运的生物学由铁的化学性质决定。游离铁在中性pH（在含氧溶液中）的水中约为10- 10 M，在磷酸盐缓冲液存在下约为10- 19 M，浓度太低而不能支持细胞活力。因此，从铁从食物来源中释放到其在细胞中的最终分布，铁必须从一种螯合剂“传递”到另一种螯合剂。螯合作用的失败，相当于铁向还原剂或氧化剂的呈递，导致反应性化学，而适当的螯合作用溶解并保护铁免受氧化态变化的影响。在过去的十年中，一系列的铁螯合剂，载体和转运蛋白（蛋白质和有机分子）已被确定，影响铁从肠腔交换到身体的几乎每个细胞，即使在中性pH值，在氧气的存在下。这些蛋白质和有机分子提供短程运输（穿过细胞膜）和长程运输（通过循环），以将足够量的铁递送到靶细胞并从受损细胞中回收铁。几乎没有铁流失到环境中，这意味着可以通过有限的补充（人类每天约1毫克）保持稳定状态。这意味着捕获和贩运途径是有效的，并遏制了铁向环境的出口。捕获和回收铁的机制已被描述，并已在十二指肠细胞或巨噬细胞中进行了最重要的研究。然而，许多携带铁的蛋白质被过滤到肾单位中，众所周知，急性和慢性肾损伤会导致尿液中出现铁，从而导致催化铁介导的损伤。为了了解肾脏中的铁运输，需要分析铁运输蛋白在许多细胞类型中的沿着的过程。 肾单位我已经确定了这些蛋白质在肾单位中的典型和非典型定位，我建议了解它们如何从尿液中去除铁并将其安全地运输到血液中。我的实验室拥有这些研究所需的专业知识和所有标准工具，例如一系列铁转运蛋白基因，新型Cre驱动程序和装载铁的示踪剂，以检测不同转运蛋白缺失时细胞和尿液铁的位置。我们的初步研究结果表明，近端和远端肾单位的机制都在发挥作用，以捕获铁，包括完全出乎意料的机制，管腔铁交通。初步结果还表明，肾脏铁运输可能受到铁调素的控制，这意味着与肝脏、十二指肠和巨噬细胞一样，肾脏不仅参与局部铁运输，而且可能是全身铁平衡的贡献者。从拟议的研究结果将提供铁介导的急性肾损伤的分子意义。