Renal Injury and Adaptation to Heme Proteins

血红素加氧酶(HO)将血红素转化为胆绿素，在此过程中铁被释放，一氧化碳被释放。 (CO)被释放；胆绿素还原酶随后将胆绿素转化为胆红素。1992年，派的办公室 提供了HO-1具有细胞保护作用的第一个证据，这一发现源于急性肾组织中的血红素介导 这是1993-1997年供资周期的基础；1997-2002年周期是基于 PI的实验室发现，HO-1在其他形式的肾脏损伤中具有细胞保护作用。2002-2007年度 Cycle试图确定被HO-1中断的致病途径，并与相关的 HO系统抑制：i)血管收缩/缺血，li)炎症，以及iii) 细胞凋亡。拟议的目标延续了这些调查主题。AIM我将描述何俊仁的角色 通过检测全身和肾脏血流动力学效应对抗血管收缩的系统 HO-1“‘和HO^”小鼠的血管收缩(DOCA模型)。 这一目标将研究NADPH氧化酶、超氧阴离子产生、BH4/BH2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品在多大程度上 当HO-1或HO-2缺乏时，HO可逆转增强的血管收缩。AIM II将决定 HO系统对内毒素诱导的炎症的抗炎作用基础，靶向性 核因子-kB的激活是HO抗炎作用的关键部位。这些研究将确定 HO-1通过改变核因子-KB的激活来调节炎症反应的程度； 特异性核因子-KB依赖的细胞因子(MCP-1、IL-6、IL-12(P40)和肿瘤坏死因子)对被夸大的 HO-1缺乏引起的炎症；特定HO产品的抗炎能力以及是否 这些产物影响核因子-KB的激活，最终，HO-1过表达抑制内毒素-1的能力。 引发炎症。AIM 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“‘”小鼠的肾缺血模型中，IL-6及其信号转导物种pSTAT3rthe 现在在肾脏中被确认为促细胞凋亡。IL-6Is在肾脏显著而独特地诱导，Iung7和Iung7 心脏，并在血清中增加。在这个细胞凋亡模型中，抑制IL-6/pSTAT3的作用将是 下定决心。这一目标还将确定IL-6在肾脏和体循环中的来源，以及 HO-1对IL-6表达的调节作用因此，这一目标将决定IL-6^‘STAT-3^的贡献 在没有HO-1的情况下，细胞凋亡和其他缺血的不良影响，以及交互作用 IL-6和HO-1的细胞表达与信号转导之间的关系。LAV摘要。此应用程序旨在 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袭。 这一认识可能有助于开发治疗肾脏疾病的新疗法。

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.