Role of apolipoprotein M in acute kidney injury

载脂蛋白M在急性肾损伤中的作用

• 批准号: 7690144
• 负责人: DIDIER PORTILLA
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690144
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Apolipoproteins; Apoptotic; Biological Markers; Blood Urea Nitrogen; Cell Death; Cell Line; Cells; Cisplatin; Complication; Creatinine; Development; Event; Excretory function; Fibrates; Healthcare; High Density Lipoproteins; Hormonal; Hyperinsulinism; Hyperlipidemia; Hypoxia; Impairment; In Vitro; Inflammation; Inflammatory; Injury; Insulin Resistance; Ischemia; Kidney; Knockout Mice; Laboratories; Length of Stay; Ligands; Lipids; Lipoproteins; Liver; Mediating; Metabolic; Morbidity - disease rate; Mus; Necrosis; PPAR alpha; Pathogenesis; Patients; Plasma; Play; Regulation; Renal function; Reperfusion Injury; Reperfusion Therapy; Role; Scheme; Serum; Tissues; Transgenic Mice; Tubular formation; Universities; Veterans; Wild Type Mouse; abstracting; combat; human APOM protein; immortalized cell; in vivo; in vivo Model; metabolomics; mortality; novel therapeutics; prevent; public health relevance; response; tool; urinary

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Our studies will focus on defining the role that kidney-derived Apolipoprotein M (ApoM) plays in lipid accumulation and proximal tubule cell death during Acute Kidney Injury (AKI). ApoM in the serum is mainly present in High Density Lipoproteins (HDL), however, ApoM is also expressed in liver and kidney tissue. Our preliminary studies show that kidney-derived ApoM is mainly expressed in the proximal tubule, and that its expression is reduced during AKI. We find also increased shedding of urinary ApoM that precedes changes in blood urea nitrogen and serum creatinine in wild type mice as well as human ApoM transgenic mice exposed to cisplatin. Since recent studies support the role of ApoM as an anti-inflammatory and anti-atherogenic lipoprotein, we plan to use wild type mice, human ApoM transgenic mice and ApoM knockout mice (available to us from the laboratory of Dr Lars Bo Nielsen, University of Copenhagen) to compare the effects of cisplatin and ischemia reperfusion injury on renal function . We will determine the effect(s) of increased expression of kidney ApoM on the influx of inflammatory cells that occurs during ischemia reperfusion and cisplatin-mediated AKI. In addition, we will determine in human ApoM transgenic mice, whether increased accumulation of kidney neutral lipids mediated by reduced expression of ApoM in the proximal tubule leads to proximal tubule cell death and ARF. We expect to see amelioration of kidney function in human ApoM transgenic mice when compared to wild type mice. Finally, we will use primary cultures obtained from human ApoM transgenic mice, or TKPTS cells (immortalized proximal tubule cell line) infected with adeno ApoM, to determine 1) the mechanisms by which increased expression of ApoM is cytoprotective, and whether the cytoprotective response of increased ApoM relates to reduced accumulation of neutral lipids, reduced apoptotic/necrotic cell death, when these proximal tubules are exposed to either cisplatin or hypoxia/ reoxygenation injury. Our preliminary studies also show that the use of PPARalpha ligand like fibrates prevent cisplatin-induced urinary shedding of kidney-derived ApoM and ameliorate kidney function. We plan to examine whether the expression, secretion and function of ApoM in proximal tubular cells in culture are different in proximal tubules isolated from PPARalpha transgenic mice when compared to proximal tubules isolated from wild type mice. Overall, our studies will contribute to a better understanding of the metabolic effects of kidney-derived apolipoprotein M, will define its role as an early biomarker of AKI, and will elucidate the protective mechanisms of increasing PPARalpha function and activity in the proximal tubule. PUBLIC HEALTH RELEVANCE: Potential Impact to Veterans Health Care: Acute kidney injury is a serious complication seen not only in combat but also in our hospitalized veteran patients, resulting in increased morbidity, mortality, and length of hospital stay. Our proposed studies will examine the role of apolipoprotein M as potential contributor to the observed accumulation of neutral lipids in kidney tissue during AKI. The use of PPARalpha ligand like fibrates offers a novel therapeutic tool to reduce kidney tissue damage, and to reduce the high morbidity and mortality associated with the development of AKI

描述(由申请人提供)： 项目摘要/摘要我们的研究将集中于确定肾源性载脂蛋白M(ApoM)在急性肾损伤(AKI)期间脂质堆积和近端小管细胞死亡中所起的作用。血清中的载脂蛋白主要存在于高密度脂蛋白中，但肝、肾组织中也有载脂蛋白的表达。我们的初步研究表明，肾源性载脂蛋白主要在近曲小管表达，在急性肾损伤过程中其表达减少。我们还发现，在暴露于顺铂的野生型小鼠和人类载脂蛋白转基因小鼠中，尿载脂蛋白排泄量增加，先于血尿素氮和血肌酐的变化。由于最近的研究支持载脂蛋白作为一种抗炎和抗动脉粥样硬化的脂蛋白的作用，我们计划使用野生型小鼠、人载脂蛋白转基因小鼠和载脂蛋白基因敲除小鼠(由哥本哈根大学Lars Bo Nielsen博士的实验室提供)来比较顺铂和缺血再灌注损伤对肾功能的影响。我们将确定(S)肾脏载脂蛋白表达增加对缺血再灌注和顺铂介导的急性肾损伤时炎症细胞流入的影响。此外，我们将在人类apom转基因小鼠中确定apom在近端小管的表达减少所介导的肾脏中性脂积累增加是否会导致近端小管细胞死亡和ARF。我们希望看到与野生型小鼠相比，人类载脂蛋白转基因小鼠的肾功能有所改善。最后，我们将使用从人apom转基因小鼠或感染了apom腺病毒的TKPTS细胞(永生化近端小管细胞系)获得的原代培养，来确定1)apom表达增加是细胞保护的机制，以及当这些近端小管暴露于顺铂或缺氧/复氧损伤时，apom增加的细胞保护反应是否与减少中性脂类积聚，减少细胞凋亡/坏死细胞死亡有关。我们的初步研究还表明，使用类似PPARpha的贝特类配体可以防止顺铂诱导的肾源性载脂蛋白尿脱落，并改善肾功能。我们计划检测培养的近端小管细胞中apom的表达、分泌和功能是否与从野生型小鼠分离的近端小管相比，从PPARpha转基因小鼠分离的近端小管中有所不同。总体而言，我们的研究将有助于更好地了解肾源性载脂蛋白M的代谢效应，将其定义为AKI的早期生物标志物，并将阐明增加PPARα功能和近端小管活性的保护机制。 公共卫生相关性： 对退伍军人医疗保健的潜在影响：急性肾损伤是一种严重的并发症，不仅在战斗中可以看到，而且在我们住院的退伍军人中也是如此，导致发病率、死亡率和住院时间的增加。我们拟开展的研究将探讨载脂蛋白M在急性肾损伤期间肾脏组织中性脂质蓄积中的潜在作用。使用类似贝特类的PPARpha配体提供了一种新的治疗工具来减少肾组织损伤，并降低与AKI发展相关的高发病率和死亡率