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.

血红素加氧酶（HO）将血红素转化为胆绿素，在此期间释放铁和一氧化碳。 (CO)胆绿素还原酶随后将胆绿素转化为胆红素。In 1992，the Pi's Pi 'laboratory实验室 提供了HO-1具有细胞保护作用的第一个证据，这一发现来源于急性肾血红素介导的 这是1993-1997年供资周期的基础; 1997-2002年周期是根据 Pi的实验室发现HO-1在其他形式的肾损伤中具有细胞保护作用。2002-2007年 循环试图确定被HO-1中断的致病途径，并证明，沿着相关的 HO系统抑制：i）血管收缩/缺血，i i）炎症，和iii） 凋亡拟议的目标延续了这些调查主题。目的我会阐述民政事务总署的角色 通过检查全身和肾脏血液动力学效应， 在HO-1+和HO-2+小鼠中的Ang II依赖性和Ang II非依赖性血管收缩（DOCA模型）。 这一目标将研究NADPH氧化酶，超氧阴离子生成，BH 4/BH 2水平等机制 和eNOS的偶联，以及内皮素-1的作用;这一目标也将决定产物在多大程度上 HO-1或HO-2缺乏时，HO的表达可逆转血管收缩反应的增强。目标二将决定 HO系统对LPS诱导的炎症的抗炎作用的基础是， NF-κ B的活化是HO抗炎作用的关键位点。这些研究将决定 HO-1通过改变NF-κ B的活化调节炎症反应的程度; 特异性NF-κ B依赖性细胞因子（MCP-1、IL-6、IL-12（p40）和TNF）对过度的 由于HO-1缺乏引起的炎症;特定HO产物的抗炎能力以及是否 这些产物影响NF-κ B的活化;最后，HO-1过表达抑制LPS的能力， 驱动炎症。目的III将研究细胞凋亡、急性肾损伤和死亡率增加的基础 在HO-1小鼠中，进行肾缺血，重点是IL-6及其信号种类，pSTAT 3r。 现在被鉴定为肾脏中的促凋亡基因。IL-6在肾脏中被显著且独特地诱导， 心脏，并在血清中增加。在这种凋亡模型中，抑制IL-6/pSTAT 3的作用将被抑制。 测定这一目的也将确定IL-6在肾脏和体循环中的来源， HO-1对IL-6表达的调控。因此，这一目标将确定IL-6、STAT-3、 细胞凋亡和其他不利影响的缺血在没有HO-1，和往复作用 IL-6和HO-1的细胞表达和信号传导之间的关系。总结。本申请旨在 了解一种名为血红素加氧酶-1的蛋白质如何保护肾脏免受不同类型疾病的侵害。 这种理解可能有助于开发肾脏疾病的新疗法。