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种流行性的公共卫生问题。CKD比糖尿病或充血性心力衰竭更多地困扰65岁以上的个体，约占老年患者的40%。对肾衰竭易感性随年龄增长而增加的假定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，即缺血通过激活肾小管上皮细胞中的促炎通路加速老年肾脏中肾病的进展，最终导致细胞凋亡、纤维化和肾衰竭。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）在缺血后炎症综合征中的重要作用。我们现在假设，全身，特别是白细胞介素（白细胞介素）-1和-6，和肾内（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，因此炎症和功能在老年糖尿病缺血后肾脏。为了直接验证我们的假设，我们提出了以下具体目标：（确定代谢紊乱和缺氧导致肾小管上皮细胞活化为促炎表型的机制。我们已经证明了在糖尿病/肥胖症的体内和暴露于促炎脂质的体外培养的肾小管上皮细胞中，肾小管上皮细胞活化为促炎状态，ICAM-1和LOX-1上调。使用这种细胞培养模型来确定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断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用途。 (To明确了老年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，系统性白细胞介素（IL）-1，IL-6，作为早期调节剂;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，是关键的ICAM-1和LOX-1在慢性肾脏疾病的肾小管表达。此外，我们提出，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将改善老年糖尿病肾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作为肾衰竭的创新疗法。拟议的研究检查了新的假设，即年龄相关的肾脏疾病的结果（至少部分）从炎症，包括介导的ICAM-1和LOX-1; IL-1，IL-6，p38 MAPK和血管紧张素II是至关重要的诱导ICAM-1和LOX-1和炎症的特异性阻断剂将导致改善功能的缺血后炎症综合征在老年肾脏。

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.