The Postischemia Inflammatory Syndrome in the Aged Kidney

描述（由申请人提供）：慢性肾脏疾病（CKD），终末期肾脏疾病及其并发症是一个流行病比例的公共卫生问题。65岁以上的慢性肾病患者比糖尿病或充血性心力衰竭患者多，约占老年患者的40%。随着年龄的增长，对肾衰竭易感性的增加的假设解释包括糖尿病和缺血的高频率。我们的初步数据支持临床相关假设，即缺血通过激活小管上皮的促炎通路，最终导致凋亡细胞死亡、纤维化和肾功能衰竭，从而加速老年肾脏肾病的进展。此外，我们已经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。我们现在假设这两种全身性介质，特别是白介素-1和-6，以及肾内（血管紧张素II和p38丝裂原活化蛋白激酶）介质调节ICAM-1和LOX-1，从而调节老年糖尿病肾缺血后的炎症和功能。为了直接验证我们的假设，我们提出以下具体目标：(确定代谢紊乱和缺氧导致小管上皮活化到促炎表型的机制。我们已经证明，在体内糖尿病/肥胖患者和体外培养的暴露于促炎脂质的肾小管上皮细胞中，ICAM-1和LOX-1的上调激活了小管上皮到促炎状态。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，将允许控制更多的因素和使用特异性阻滞剂来彻底剖析炎症和损伤的机制。我们将确定在这些细胞中诱导ICAM-1和LOX-1的关键介质，并评估抑制剂在体内的潜在应用。(明确老年ZS大鼠肾缺血后炎症综合征中肾脏炎症的机制，特别是ICAM-1和LOX-1的小管诱导。我们假设系统性白细胞介素(IL)-1和IL-6是早期的调节因子；肾内p38丝裂原活化蛋白激酶（MAPK）和血管紧张素II作为放大器，在慢性肾病肾小管中ICAM-1和LOX-1的表达中起关键作用。此外，我们提出用霉酚酸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的肾损伤。最后，我们将评估小管细胞移植作为一种治疗肾功能衰竭的创新疗法。拟议的研究检验了一个新的假设，即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在诱导ICAM-1和LOX-1中起关键作用，特异性炎症阻滞剂可改善老年肾脏缺血后炎症综合征的功能。

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.