Role of the Kidney in Iron Balance

 描述(申请人提供)：铁的运输生物学是由铁的化学决定的。在中性pH值的水中(含氧溶液)，游离铁的存在约为10-10M，在存在磷酸盐缓冲液的情况下，游离铁的存在约为10-19M，这一浓度太低，不足以支持细胞的存活。因此，从食物来源释放铁的那一刻起，直到它在细胞中的最终分布，铁必须从一种螯合剂“移交”到另一种螯合剂。在过去的十年中，已经发现了一系列的铁络合剂、载体和转运体(包括蛋白质和有机分子)，它们影响着从肠腔到身体几乎每一个细胞的铁的交换，甚至在氧气存在的情况下，在中性pH下也是如此。这些蛋白质和有机分子提供短程运输(跨细胞膜)和长程运输(通过循环)，以向靶细胞输送足够量的铁，并从受损细胞中回收铁。几乎不会对环境造成铁的损失，这意味着可以通过有限的补充(人类每天大约1毫克)来维持稳定状态。这意味着捕获和贩运途径是有效的，向环境出口的铁得到了遏制。捕获和循环铁的机制已经被描述，最重要的是在十二指肠肠细胞或巨噬细胞中进行了研究。然而，许多携带铁的蛋白质被过滤到肾单位，众所周知，急性和慢性肾脏损伤会导致尿铁出现，从而导致催化铁介导的损伤。为了了解铁在肾脏中的转运，需要分析多种细胞类型中的铁转运蛋白。 尼龙。我已经确定了这些蛋白质在肾单位的规范和非常规定位，我建议了解它们是如何从尿液空间中清除铁并将其安全地输送到血液中的。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，例如一系列铁离子转运蛋白基因、新型CRE驱动器和装载铁的示踪剂，以检测不同转运蛋白缺失时细胞和尿铁的位置。我们的初步结果表明，近端和远端的肾单位机制都在发挥作用，包括完全意想不到的腔内铁交通机制。初步结果还表明，肾脏的铁运输可能受海普西丁的控制，这意味着像肝脏、十二指肠和巨噬细胞一样，肾脏不仅参与局部铁的运输，而且很可能是全身铁平衡的贡献者。这项拟议的研究结果将为急性肾损伤中铁介导的损伤提供分子生物学意义。

 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.