The Postischemia Inflammatory Syndrome in the Aged Kidney

老年肾脏缺血后炎症综合征

• 批准号: 7949076
• 负责人: Katherine J Kelly
• 金额: $ 29.26万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7949076
• 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; Interleukins; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Lectin; Leukocytes; Lipids; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Mediator of activation protein; Metabolic; Migration Inhibitory Factor; Mitogen-Activated Protein Kinases; 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; intercellular cell adhesion molecule; 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. PUBLIC HEALTH RELEVANCE: Chronic kidney disease (CKD) in those older than 60 years has increased markedly to approximately 28% of the population. In the US, more people are afflicted with CKD than either diabetes or congestive heart failure. Nearly one-half of patient beginning dialysis for CKD were e65 yo. We propose to study inflammatory and vascular injury and cell death and the effects of potential therapies in a model of CKD.

描述（由申请人提供）：慢性肾脏疾病（CKD），末期肾脏疾病及其并发症是流行比例的公共卫生问题。 CKD比糖尿病或充血性心力衰竭更受年轻患者的糖尿病或充血性心力衰竭的患者的痛苦。假定的解释，增加了随着年龄增长的肾衰竭易感性，包括糖尿病和缺血的高频率。我们的初步数据支持了临床上相关的假设，该假设通过激活管状上皮中的促炎途径最终导致凋亡细胞死亡，纤维化和肾衰竭，从而加速了老年肾脏肾病的进展。此外，我们在该炎症后炎性综合征中证明了促炎受体间炎性受体间粘附分子1（ICAM-1）和凝集素样氧化的低密度脂蛋白受体（LOX-1）的关键作用。现在，我们假设全身性，尤其是白介素（白介素）-1和-6，以及肾内（血管紧张素II和p38有丝分裂原激活的蛋白激酶）介体介导子调节ICAM-1和LOX-1和LOX-1，因此在年龄，糖尿病后糖尿病后肾脏肾脏肾脏中的炎症和功能。为了直接检验我们的假设，我们提出了以下特定目的：（确定代谢异常和缺氧导致肾小管上皮激活的机制。我们已经表明，肾小管上皮的激活表现为对ICAM-1和Lox-1 renity and Intive in verro and in vyivo in viivo in viivo in viivo in viivo in viivo in viivo in viivo in viivo中的激活暴露于促炎脂质的管状细胞使用这种细胞培养模型来定义ICAM-1和LOX-1调节的机制，并且功能的改变将使更多的因素和使用特定的阻滞剂彻底解剖炎症的机制老年ZS大鼠肾脏的肾脏后炎症综合征中肾脏炎症的机制，尤其是ICAM-1和LOX-1的管状诱导。我们假设系统性白介素（IL）-1，IL-6为早期调节剂。肾内p38损伤激活蛋白激酶（MAPK）和血管紧张素II（作为放大器）在慢性肾脏疾病的肾小管中至关重要。此外，我们提出，通过霉酚酸酯莫夫蒂尔或对ICAM-1，IL-1，血管紧张素II或p38 MAPK的特异性抑制阻塞炎症将在衰老后炎性肾脏中炎性综合征的肾脏损伤来减轻肾脏损伤。最后，我们将评估管状细胞移植作为肾衰竭的创新疗法。拟议的研究研究了新的假设，即炎症与年龄相关的肾脏疾病结果（至少部分），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在诱导ICAM-1和LOX-1方面至关重要，并且炎症的特定阻滞剂将改善老年肾脏的炎症后炎症综合征的功能。 公共卫生相关性：60岁以上的慢性肾脏疾病（CKD）显着增加到大约28％的人口。在美国，比糖尿病或充血性心力衰竭患有CKD的人更多。 CKD开始透析的近一半患者是E65 YO。我们建议研究CKD模型中潜在疗法的炎症和血管损伤以及细胞死亡的影响。