The Postischemia Inflammatory Syndrome in the Aged Kidney

老年肾脏缺血后炎症综合征

• 批准号: 8723805
• 负责人: Katherine J Kelly
• 金额: $ 28.97万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723805
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adhesions; Age; Aging; Amplifiers; Angiotensin II; Apoptosis; Apoptotic; Blood Vessels; Cell Culture Techniques; Cell Death; Cell Transplantation; Cells; Chronic; Chronic Kidney Failure; Congestive Heart Failure; Data; Diabetes Mellitus; Dialysis procedure; Disease Progression; End stage renal failure; Epidemic; Epithelial; Epithelial Cells; Epithelium; Fibrosis; Frequencies; Functional disorder; Glucose; Head; Heart failure; Hypoxia; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Innovative Therapy; Intercellular adhesion molecule 1; Interleukin-1; Interleukin-6; Ischemia; Kidney; Kidney Diseases; Kidney Failure; LOX gene; Lectin; Leukocytes; Lipids; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Mediator of activation protein; Metabolic; Migration Inhibitory Factor; Modeling; Nephrotoxic; Obesity; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Proteinuria; Public Health; Rattus; Regulation; Renal function; Renal tubule structure; Reporting; Risk; Role; Syndrome; System; Systemic disease; Techniques; Testing; Therapeutic Effect; Transplantation; Tubular formation; Up-Regulation; adhesion receptor; age related; aged; attenuation; clinically relevant; cytokine; diabetic; human MAPK14 protein; human old age (65+); improved functioning; in vivo; inhibitor/antagonist; intravital microscopy; loss of function; mycophenolate mofetil; novel; older patient; oxidized low density lipoprotein; public health relevance; receptor; response; urinary

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD), end stage renal disease and their complications are a public health problem of epidemic proportions. CKD afflicts more individuals over 65 years old than diabetes or congestive heart failure, approximately 40% of older patients. Postulated explanations for increased susceptibility to renal failure with increasing age include the high frequency of diabetes and ischemia. Our preliminary data support the clinically relevant hypothesis that ischemia accelerates the progression of nephropathy in the aged kidney by activating proinflammatory pathways in tubular epithelia ultimately resulting in apoptotic cell death, fibrosis and renal failure. Furthermore, we have demonstrated critical roles for the proinflammatory receptors intercellular adhesion molecule-1 (ICAM-1) and lectin-like oxidized low density lipoprotein receptor (LOX-1) in this postischemia inflammatory syndrome. We now postulate that both systemic, particularly interleukins (interleukin)-1 and -6, and intrarenal (angiotensin II and p38 mitogen activated protein kinase) mediators regulate ICAM-1 and LOX-1 and therefore inflammation and function in the aged, diabetic postischemia kidney. To directly test our hypotheses, we propose the following specific aims: (To determine the mechanisms by which metabolic derangements and hypoxia result in tubular epithelial activation to a proinflammatory phenotype. We have demonstrated activation of tubular epithelia to a proinflammatory state with upregulation of ICAM-1 and LOX-1 both in vivo in diabetes/obesity and in vitro in cultured renal tubular epithelial cells exposed to proinflammatory lipids. Using this cell culture model to define the mechanisms of ICAM-1 and LOX-1 regulation and alteration of function will allow control of more factors and the use of specific blockers to thoroughly dissect the mechanisms of inflammation and injury. We will determine the key mediators of induction of ICAM-1 and LOX-1 in these cells and evaluate inhibitors for potential use in vivo. (To define the mechanisms of renal inflammation, particularly tubular induction of ICAM-1 and LOX-1, in the postischemia inflammatory syndrome in the aged ZS rat kidney. We hypothesize that systemic interleukin (IL)-1, IL-6, as early regulators; and intrarenal p38 mitogen activated protein kinase (MAPK) and angiotensin II, as amplifiers, are critical in ICAM-1 and LOX-1 expression in renal tubules in chronic kidney disease. Furthermore, we propose that blocking inflammation with mycophenolate mofetil or specific inhibition of ICAM-1, IL-1, angiotensin II or p38 MAPK will ameliorate renal injury in the postischemia inflammatory syndrome in the aging, diabetic kidney. Finally, we will evaluate tubular cell transplantation as an innovative therapy for renal failure. The proposed studies examine the novel hypothesis that age-related renal disease results (at least in part) from inflammation, including that mediated by ICAM-1 and LOX-1; that IL-1, IL-6, p38 MAPK and angiotensin II are critical in the induction of ICAM-1 and LOX-1 and that specific blockers of inflammation will result in improved function in the postischemia inflammatory syndrome in the aged kidney.

描述（由申请人提供）：慢性肾病（CKD）、终末期肾病及其并发症是一个流行性的公共卫生问题。与糖尿病或充血性心力衰竭相比，65 岁以上的 CKD 患者更多，约占老年患者的 40%。随着年龄的增长，肾衰竭的易感性增加，推测的解释包括糖尿病和缺血的高发率。我们的初步数据支持临床相关的假设，即缺血通过激活肾小管上皮中的促炎途径，最终导致细胞凋亡、纤维化和肾衰竭，从而加速老年肾脏肾病的进展。此外，我们还证明了促炎受体细胞间粘附分子-1 (ICAM-1) 和凝集素样氧化低密度脂蛋白受体 (LOX-1) 在这种缺血后炎症综合征中的关键作用。我们现在假设全身介质，特别是白细胞介素 (interleukin)-1 和 -6，以及肾内介质（血管紧张素 II 和 p38 丝裂原激活蛋白激酶）调节 ICAM-1 和 LOX-1，从而调节老年糖尿病缺血后肾脏的炎症和功能。为了直接检验我们的假设，我们提出以下具体目标：（确定代谢紊乱和缺氧导致肾小管上皮激活为促炎表型的机制。我们已经证明，在糖尿病/肥胖体内和体外培养肾中，ICAM-1和LOX-1上调可将肾小管上皮激活为促炎状态。 肾小管上皮细胞暴露于促炎脂质。使用这种细胞培养模型来定义 ICAM-1 和 LOX-1 调节和功能改变的机制将允许控制更多因素并使用特定的阻断剂来彻底剖析炎症和损伤的机制。我们将确定这些细胞中诱导 ICAM-1 和 LOX-1 的关键介质，并评估抑制剂在体内的潜在用途。 （定义 老年 ZS 大鼠肾脏缺血后炎症综合征中肾脏炎症的机制，特别是 ICAM-1 和 LOX-1 的肾小管诱导。我们假设全身白细胞介素 (IL)-1、IL-6 作为早期调节因子；肾内 p38 丝裂原激活蛋白激酶 (MAPK) 和血管紧张素 II 作为放大器，在 慢性肾脏病肾小管中 ICAM-1 和 LOX-1 的表达。此外，我们建议用吗替麦考酚酯阻断炎症或特异性抑制 ICAM-1、IL-1、血管紧张素 II 或 p38 MAPK 将改善衰老糖尿病肾脏缺血后炎症综合征中的肾损伤。最后，我们将评估肾小管细胞移植 肾衰竭的创新疗法。拟议的研究检验了一个新的假设，即与年龄相关的肾脏疾病（至少部分）是由炎症引起的，包括由 ICAM-1 和 LOX-1 介导的炎症； IL-1、IL-6、p38 MAPK 和血管紧张素 II 对于 ICAM-1 和 LOX-1 的诱导至关重要，并且特定的炎症阻滞剂将改善缺血后炎症综合征的功能 衰老的肾脏。