APOC3 mediated dyslipidemia in diabetic kidney disease and atherosclerosis

APOC3 介导的糖尿病肾病和动脉粥样硬化中的血脂异常

• 批准号: 10337327
• 负责人: Jenny E. Kanter
• 金额: $ 38.83万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-17 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337327
• 关键词: Acceleration; Adult; Affect; Albuminuria; Antisense Oligonucleotides; Apolipoproteins; Atherosclerosis; Attenuated; Blood Glucose; Cardiovascular Diseases; Cause of Death; Cells; Chylomicrons; Complement; Complement 3a; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Data; Dependovirus; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dyslipidemias; Endothelial Cells; Epidemic; Exposure to; Future; Hepatic; High Density Lipoproteins; Human; Hypertriglyceridemia; Impaired Renal Function; Impairment; In Vitro; Infiltration; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; LDL Cholesterol Lipoproteins; Life; Link; Lipids; Lipoproteins; Liver; Mediating; Metabolism; Modeling; Mus; Myeloid Cells; Nephrectomy; Non-Insulin-Dependent Diabetes Mellitus; Patients; Persons; Pharmacologic Substance; Phenotype; Plasma; Play; Population; Process; Renal function; Residual state; Risk; Risk Factors; Role; Serum; Severity of illness; Techniques; Testing; Triglycerides; Very low density lipoprotein; cardiovascular disorder risk; chemokine receptor; diabetic; inhibitor; macrophage; monocyte; mouse model; new therapeutic target; non-diabetic; novel; novel therapeutics; overexpression; podocyte; prevent; recruit; targeted treatment; therapeutic target; transcription factor

People with diabetes are more likely to have cardiovascular disease (CVD) and kidney disease. The majority of the excess risk of CVD in diabetes is restricted to patients with diabetes and diabetic kidney disease (DKD). New data indicates that apolipoprotein C3 (APOC3) plays a critical role in diabetic atherosclerosis and preliminary data suggests that it is causally linked to DKD. APOC3 is a key regulator of triglyceride-rich lipoprotein (TLR) metabolism. It is in turn regulated by insulin, but also by kidney disease. Our overall hypothesis is that diabetes and kidney disease raise APOC3 levels. Increased levels of TRLs and their remnants, driven by APOC3, accelerate diabetic kidney disease as well as atherosclerosis. This hypothesis will be tested in 2 separate aims: Aim 1: Does blocking APOC3 prevent diabetic kidney disease? This will be tested in 2 different mouse models of diabetes and kidney disease using 2 different approaches to target APOC3; a specific antisense (ASO) to APCO3 and a transcription factor (CREBH) that has profound effects selectively on TLR-associated APOC3. Aim 2: Does renal impairment and diabetes act synergistically to elevate APOC3, contributing atherosclerosis? To test the hypothesis that diabetes and reduced renal function act synergistically to elevate plasma APOC3 to accelerate atherosclerosis we will induce renal impairment in non-diabetic and diabetic mice using 5/6 nephrectomy. APOC3 levels will be reduced in these mice using both APOC3 ASO treatment and hepatic overexpression of CREBH to test the causal role of APOC3. The majority of the excessive CVD risk in diabetes is present in patients who also have DKD. With the diabetic population growing, finding new therapeutic targets is exceedingly important. We propose a novel common mechanism whereby DKD and CVD are accelerated by APOC3-mediated increases in TRLs and their remnants, and a new way that both can be prevented by blocking APOC3. These studies are likely to reveal important similarities in the mechanisms whereby APOC3 promotes two of the major complications of diabetes. A human APOC3 ASO has already been tested in T2DM patients with promising TRL-lowering results, thus APOC3 might be a therapeutic target for combating the rising epidemic of diabetic complications.

糖尿病患者更容易患心血管疾病（CVD）和肾脏疾病。大多数 糖尿病中CVD的过度风险仅限于患有糖尿病和糖尿病肾病（DKD）的患者。 新的数据表明，载脂蛋白C3（APOC 3）在糖尿病动脉粥样硬化中起着关键作用， 初步数据表明，它与DKD有因果关系。APOC 3是富含磷脂酰肌醇的 脂蛋白（TLR）代谢。它反过来又受胰岛素调节，但也受肾脏疾病调节。我们的整体 假设糖尿病和肾脏疾病会提高APOC 3水平。TRL水平的增加及其 由APOC 3驱动的残余物加速糖尿病肾病以及动脉粥样硬化。这一假设将 在2个不同的目标中进行测试：目标1：阻断APOC 3可以预防糖尿病肾病吗？这将是 在2种不同的糖尿病和肾脏疾病小鼠模型中使用2种不同的靶向方法进行测试， APOC 3;一种对APCO 3和转录因子（CREBH）具有深远影响的特异性反义（阿索） 选择性作用于TLR相关的APOC 3。目的2：肾损害和糖尿病是否协同作用， 升高APOC 3，导致动脉粥样硬化？为了验证糖尿病和肾功能下降 协同作用，提高血浆载脂蛋白C 3，加速动脉粥样硬化， 非糖尿病和糖尿病小鼠使用5/6肾切除术。在这些小鼠中，APOC 3水平将降低， APOC 3阿索治疗和CREBH的肝脏过表达以测试APOC 3的因果作用。大多数 糖尿病中心血管疾病风险过高的患者也存在DKD。糖尿病人群 寻找新的治疗靶点非常重要。我们提出了一种新的通用机制 其中DKD和CVD通过APOC 3介导的TRL及其残余物的增加而加速， 这两种疾病都可以通过阻断APOC 3来预防。这些研究可能揭示重要的 APOC 3促进糖尿病两种主要并发症的机制相似。人类 APOC 3阿索已经在T2 DM患者中进行了测试，具有有希望的降低TRL的结果，因此APOC 3 ASO 可能是对抗糖尿病并发症流行的治疗靶点。