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: 10713362
• 负责人: Jenny E. Kanter
• 金额: $ 9.8万
• 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/10713362
• 关键词: Acceleration; Adult; Affect; Albuminuria; Antisense Oligonucleotides; Apolipoproteins; Atherosclerosis; Attenuated; Blood Glucose; Cardiovascular Diseases; Cause of Death; Cells; Chylomicrons; Complement; 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; Macrophage; Mediating; Metabolism; Modeling; Mus; Myeloid Cells; Nephrectomy; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; 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; 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.

糖尿病患者更有可能患有心血管疾病 (CVD) 和肾脏疾病。大部分 糖尿病引起的 CVD 风险过高仅限于患有糖尿病和糖尿病肾病 (DKD) 的患者。 新数据表明载脂蛋白 C3 (APOC3) 在糖尿病动脉粥样硬化和 初步数据表明，它与 DKD 存在因果关系。 APOC3 是富含甘油三酯的关键调节因子 脂蛋白（TLR）代谢。它反过来又受到胰岛素的调节，也受到肾脏疾病的调节。我们的整体 假设糖尿病和肾脏疾病会提高 APOC3 水平。 TRL 水平及其影响的增加 APOC3 驱动的残余物会加速糖尿病肾病和动脉粥样硬化。这个假设将 在 2 个不同的目标中进行测试： 目标 1：阻断 APOC3 是否可以预防糖尿病肾病？这将是 使用 2 种不同的靶向方法在 2 种不同的糖尿病和肾病小鼠模型中进行测试 APOC3； APCO3 的特异性反义 (ASO) 和具有深远影响的转录因子 (CREBH) 选择性地作用于 TLR 相关的 APOC3。目标 2：肾功能损害和糖尿病是否具有协同作用 APOC3升高，导致动脉粥样硬化？检验糖尿病与肾功能下降的假设 协同作用，升高血浆APOC3，加速动脉粥样硬化，我们将诱发肾功能损害 使用 5/6 肾切除术的非糖尿病和糖尿病小鼠。使用这两种方法将降低这些小鼠的 APOC3 水平 APOC3 ASO 处理和 CREBH 肝脏过度表达，以测试 APOC3 的因果作用。大多数 糖尿病患者的 CVD 风险过高也存在于患有 DKD 的患者中。与糖尿病人群 随着疾病的不断发展，寻找新的治疗靶点显得尤为重要。我们提出了一种新颖的通用机制 APOC3 介导的 TRL 及其残余物的增加会加速 DKD 和 CVD，并且 通过阻止 APOC3 可以预防这两种情况的新方法。这些研究可能会揭示重要的 APOC3 促进糖尿病两种主要并发症的机制有相似之处。一个人类 APOC3 ASO 已在 T2DM 患者中进行了测试，具有有望降低 TRL 的结果，因此 APOC3 可能是对抗日益流行的糖尿病并发症的治疗目标。