Renal Injury and Adaptation to Heme Proteins

肾损伤和对血红素蛋白的适应

• 批准号: 7903739
• 负责人: KARL A. NATH
• 金额: $ 9.96万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903739
• 关键词: Acute; Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Bilirubin; Biliverdin reductase; Biliverdine; Blood Circulation; CCL2 gene; Carbon Monoxide; Coupling; Development; Disease; Endothelin-1; Funding; Generations; Heart; Heme; Hemeproteins; Inflammation; Inflammatory Response; Injury; Interleukin-6; Iron; Ischemia; Kidney; Kidney Diseases; Laboratories; Mediating; Modeling; Mus; NADPH Oxidase; Oxygenases; Pathway interactions; Proteins; Regulation; Role; Serum; Signal Transduction; Source; Superoxides; System; TNF gene; base; cytokine; heme oxygenase-1; heme oxygenase-2; hemodynamics; insight; mortality; overexpression; renal ischemia; vasoconstriction

Heme oxygenase (HO) converts heme to biliverdin during which iron is released and carbon monoxide (CO) is emitted; biliverdin reductase subsequently converts biliverdin to bilirubin. In 1992, the Pi'slaboratory provided the first evidence that HO-1 was cytoprotective, a finding derived in acute renal heme-mediated injury, and which was the basis for the 1993-1997 funding cycle; the 1997-2002 cycle was based on the finding by the Pi's laboratory that HO-1 was cytoprotective in other forms of renal injury. The 2002-2007 cycle sought to identify pathogenetic pathways interrupted by HO-1, and demonstrated, along with relevant mechanistic insights, that the HO system inhibits: i) vasoconstriction/ischemia, li) inflammation, and iii) apoptosis. The proposed aims continue these investigative themes. Aim I will delineate the role of the HO system in militating against vasoconstriction by examining the systemic and renal hemodynamic effects of Ang ll-dependent and Ang ll-independent vasoconstriction (theDOCA model) in HO-1"'" and HO^" mice. This aim will examine such mechanisms as NADPH oxidase, superoxide anion generation, BH4/BH2 levels and coupling of eNOS, and the role of endothelin-1; this aim will also determine the extent to which products of HO can reverse the enhanced vasoconstriction when HO-1 or HO-2 is deficient. Aim II will determine the basis for the anti-inflammatory effect of the HO system against LPS-induced_inflammation, targeting activation of NF-KB as a critical locus for the anti-inflammatory effects of HO. These studies will determine the following: the extent to which HO-1 regulates inflammatory responses by altering activation of NF-KB;the contribution of specific NF-KB-dependent cytokines (MCP-1, IL-6,IL-12(p40), and TNF) to the exaggerated inflammation due to HO-1 deficiency; the anti-inflammatory capacity of specific HO products and whether such products influence NF-KB activation; and finally, the capacity of HO-1 overexpression to inhibit LPS- driven inflammation. Aim III will examine the basis for apoptosis, acute renal injury, and increased mortality in HO-1"'" mice, subjected to renal ischemia, focusing on IL-6 and its signaling species, pSTAT3rthe .latter now identified as proapoptotic in the kidney. IL-6is markedly and uniquely induced in the kidney, Iung7 arid heart, and increased in the serum. In this model of apoptosis, the effect of inhibiting IL-6/pSTAT3 will Jbe determined. This aim will also determine th$ source of IL-6 in the kidney and systemic circulation, arid the regulation of IL-6expression by HO-1. This aim will thus determine the contribution of IL-6^'STAT-3^ apoptosis and other adverse effects of ischemia in the absence of HO-1, and the reciprocating effects between cellular expression and signaling of IL-6and HO-1. Lav Summary. This application seeks to understand how a protein called heme oxygenase-1 protects the kidney against different types of diseases. This understanding may facilitate the development of new therapies for kidney disease.

血红素氧化酶（HO）将血红素转换为双脂蛋白，在此释放铁和一氧化碳 （CO）发射； biliverdin还原酶随后将biliverdin转化为胆红素。 1992年，Pi'slaboration 提供了第一个证据表明HO-1是细胞保护的，这一发现是在急性肾血红素介导的 受伤，这是1993 - 1997年融资周期的基础； 1997-2002周期是基于 PI的实验室发现HO-1在其他形式的肾脏损伤中受到了细胞保护作用。 2002-2007 循环试图识别由HO-1中断的致病途径，并证明 机械洞察力，HO系统抑制了：i）血管收缩/缺血，li）炎症，iii） 凋亡。拟议的目标继续这些调查主题。目的，我将描述Ho的角色 通过检查系统性和肾脏血流动力学作用的系统来抵抗血管收缩的系统 HO-1“'”和HO^“小鼠中的ANG LL依赖性和ANG LL独立的血管收缩（Thedoca模型）。 该目标将检查NADPH氧化酶，超氧化阴离子的产生，BH4/BH2水平等机制 eNOS的耦合以及内皮素-1的作用；这个目标还将确定哪种产品的程度 当HO-1或HO-2不足时，HO可以逆转增强的血管收缩。 AIM II将确定 HO系统对LPS-inded_inflammation的抗炎作用的基础，靶向 NF-KB的激活是HO的抗炎作用的关键基因座。这些研究将确定 以下内容：HO-1通过改变NF-KB的激活来调节炎症反应的程度； 特异性NF-KB依赖性细胞因子（MCP-1，IL-6，IL-12（P40）和TNF）对夸张的贡献 由于HO-1缺乏引起的炎症；特定HO产品的抗炎能力以及是否 这样的产品影响NF-KB激活；最后，HO-1过表达抑制LPS-的能力 驱动的炎症。 AIM III将检查凋亡，急性肾脏损伤和死亡率增加的基础 在HO-1“”小鼠中，受到肾脏缺血的作用，重点是IL-6及其信号传导物种，PSTAT3RTHE。 现在在肾脏中被确定为凋亡。 IL-6在肾脏中明显而独特地引起iung7干旱 心脏，在血清中增加。在这种凋亡模型中，抑制IL-6/pSTAT3的效果将JBE 决定。这个目标还将确定肾脏和系统循环中IL-6的来源，干旱 通过HO-1调节IL-6表达。因此，此目标将决定IL-6^'Stat-3^的贡献 在没有HO-1的情况下，缺血的凋亡和其他不良影响，以及往复效应 在IL-6和HO-1的细胞表达和信号之间。 LAV摘要。本申请寻求 了解一种称为血红素氧酶-1的蛋白质如何保护肾脏免受不同类型的疾病的影响。 这种理解可能有助于开发用于肾脏疾病的新疗法。