The Postischemia Inflammatory Syndrome in the Aged Kidney

描述(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。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，肾功能衰竭的易感性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了临床相关假说，即缺血通过激活肾小管上皮细胞中的促炎通路，最终导致细胞凋亡、纤维化和肾功能衰竭，从而加速老年肾脏疾病的进展。此外，我们还证实了前炎症受体细胞间黏附分子-1(ICAM-1)和凝集素样氧化型低密度脂蛋白受体(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，在老年糖尿病缺血后肾脏中，全身，特别是白介素1和白介素6和肾内介质(血管紧张素II和p38丝裂原激活蛋白激酶)调节ICAM-1和LOX-1，从而调节炎症和功能。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。在糖尿病/肥胖症患者体内和体外培养的肾小管上皮细胞暴露于促炎症脂类的情况下，我们都证实了肾小管上皮细胞活化到促炎状态，同时ICAM-1和LOX-1表达上调。使用这种细胞培养模型来确定ICAM-1和LOX-1的调控机制和功能改变，将允许控制更多的因素和使用特定的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，并评估可能在体内使用的抑制剂。(目的)探讨老年ZS大鼠肾缺血后炎症综合征中肾脏炎症的机制，尤其是肾小管上皮细胞间黏附分子-1和脂氧合酶-1的诱导。我们推测，IL-1、IL-6作为早期调节因子，肾内p38丝裂原活化蛋白激酶(MAPK)和血管紧张素II(Ang II)作为扩增物，在慢性肾脏疾病肾小管ICAM-1和LOX-1表达中起关键作用。此外，我们认为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p38MAPK将改善老年糖尿病肾脏缺血后炎症综合征的肾脏损伤。最后，我们将评估肾小管细胞移植作为治疗肾功能衰竭的创新疗法。建议的研究检验了新的假设，即年龄相关性肾脏疾病(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、p38MAPK和血管紧张素II在诱导ICAM-1和LOX-1方面起关键作用；特定的炎症阻滞剂将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.