RAGE and Glomerulosclerosis

RAGE 和肾小球硬化

• 批准号: 6904631
• 负责人: VIVETTE D'AGATI
• 金额: $ 32.37万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6904631
• 关键词: biological signal transduction; blood chemistry; cell surface receptors; disease /disorder etiology; doxorubicin; electron microscopy; fluorescence microscopy; genetically modified animals; glomerulosclerosis; immunocytochemistry; laboratory mouse; oxidative stress; pathologic process; polymerase chain reaction; receptor expression; terminal nick end labeling; urinalysis; western blottings

DESCRIPTION (provided by applicant): Glomerulosclerosis (GS) is a pathological process characterized by expansion of the glomerulus secondary to increased accumulation of mesangial matrix and scarring/fibrosis of the tubulointerstitium; processes that may lead to proteinuria and renal failure. Once set in motion, processes underlying GS are usually irreversible; thus, identification of early pathogenic events is a key step in their prevention/treatment. Key roles for glomerular epithelial cells, or podocytes, in the pathogenesis of glomerular diseases are speculated, as early events in GS include progressive podocyte damage, and finally, irreversible loss. Receptor for AGE RAGE) is expressed at low levels in the normal human/mouse kidney in homeostasis, where glomerular expression is limited largely to the podocyte, and in disease settings, RAGE is expressed in infiltrating inflammatory cells such as mononuclear phagocytes (MPs), and, in addition, expression of RAGE is enhanced in the podocyte, beyond that observed at baseline. In human and murine (db/db) diabetes, and subsequent to adriamycin (ADR) exposure in BALB/c mice, expression of podocyte RAGE is increased, in parallel with increased expression of RAGE ligands, Advanced Glycation Endproducts; and proinflammatory S100/calgranulins, especially in infiltrating MP. Administration of soluble (s) RAGE to BALB/c mice exposed to ADR suppressed enlargement of the kidney; glomerular and mesangial expansion; and thickening 3f the GBM, in parallel with decreased albuminuria. We hypothesize that activation of podocyte and/or MP RAGE triggers cellular perturbation in the ADR-treated kidney, leading to enhanced permeability and inflammation early after injury; events that augur the development of oxidant stress, generation of cytokines and growth factors linked to fibrosis at later stages after ADR. We will dissect the effects of RAGE in the development/progression of GS in a murine model of ADR-induced nephropathy employing RAGE null (0) mice and transgenic mice expressing inactivated RAGE in podocytes or cells of MP lineage. We propose that identification of RAGE-dependent mechanisms in glomerular diseases may lead to novel therapies to prevent, stabilize or reverse the course of chronic GS.

描述（由申请人提供）：肾小球硬化症（GS）是一种病理过程，其特征是肾小球膨胀是肾小球基质的积累增加和肾小管间隙的疤痕/纤维化的增加；可能导致蛋白尿和肾衰竭的过程。一旦开始运动，GS的基础过程通常是不可逆转的。因此，鉴定早期致病事件是预防/治疗的关键步骤。猜测肾小球上皮细胞或足细胞的关键作用在肾小球疾病的发病机理中被推测，因为GS中的早期事件包括进行性足细胞损伤，最后是不可逆的损失。在正常的人/小鼠肾脏中，肾小球表达在很大程度上限制在足面的人/小鼠肾脏中，在低水平上表达了受体，在疾病环境中，肾小球表达在很大程度上限制在疾病环境中，在浸润性炎症细胞（如单核吞噬细胞（MPS）（MPS）（MPS）中，以及在Rage中的表达增强了Podocyce，愤怒表达。在BALB/C小鼠中的Adrimycin（ADR）暴露之后，在人和鼠（DB/DB）糖尿病中，足细胞rage的表达增加，与愤怒配体的表达增加，晚期糖基化的前产物的表达同步。和促炎S100/加州素蛋白，尤其是在浸润MP中。对暴露于ADR的BALB/C小鼠的可溶性愤怒抑制了肾脏的扩大；肾小球和肾小球膨胀；并与蛋白尿降低并联3F GBM增厚。我们假设足细胞和/或MP愤怒的激活会触发经ADR治疗的肾脏中的细胞扰动，从而在损伤后尽早增加了渗透性和炎症。增强氧化应激的发展，细胞因子的产生和与ADR后期纤维化相关的生长因子的事件。我们将在ADR诱导的肾病模型中剖析愤怒对GS发育/进展的影响，该模型采用了rage null（0）小鼠（0）小鼠和表达MP lineage的rage rage rage的转基因小鼠和转基因小鼠。我们建议鉴定肾小球疾病中的愤怒依赖性机制可能会导致新的疗法，以预防，稳定或逆转慢性GS的过程。