APOC3 mediated dyslipidemia in diabetic kidney disease and atherosclerosis

A.受资助的父母赠款或项目的摘要或摘要 糖尿病患者更容易患心血管疾病(CVD)和肾脏疾病。大多数 糖尿病中心血管疾病的额外风险仅限于糖尿病和糖尿病肾病(DKD)患者。新的 研究表明载脂蛋白C3(APOC3)在糖尿病动脉粥样硬化中起重要作用。 数据表明，它与DKD有因果关系。载脂蛋白3是富含甘油三酯的脂蛋白(TRL)的关键调节因子 新陈代谢。它不仅受胰岛素的调节，还受肾脏疾病的影响。我们的总体假设是糖尿病 肾脏疾病会增加载脂蛋白C3的水平。在APOC3的推动下，TRL及其残留物水平增加， 加速糖尿病肾病和动脉粥样硬化。这一假设将在两个不同的 目的：目的1：阻断载脂蛋白C3能否预防糖尿病肾病？这将在两个不同的地方进行测试 使用两种不同的方法靶向APOC3的糖尿病和肾脏疾病的小鼠模型； APOC3的反义(ASO)和对TRL-3有深刻影响的转录因子(CREBH)- 相关APOC3。目标2：肾损害和糖尿病是否协同作用升高载脂蛋白C3， 导致动脉粥样硬化？来检验糖尿病和肾功能减退起作用的假设 协同升高血浆载脂蛋白C3以加速动脉粥样硬化，我们将在非 糖尿病小鼠和糖尿病小鼠采用5/6肾切除术。使用这两种药物的小鼠的载脂蛋白C3水平将会降低 APOC3 ASO治疗和肝脏CREBH的过度表达，以检验APOC3的因果作用。大多数人 糖尿病中心血管疾病风险过高的风险存在于同时患有DKD的患者中。与糖尿病人群 不断发展，寻找新的治疗靶点是极其重要的。我们提出了一种新的通用机制 由此，DKD和CVD通过APOC3介导的TRL及其残留物的增加而加速，并且 可以通过阻止APOC3来阻止这两种情况的新方法。这些研究很可能揭示出重要的 APOC3促进糖尿病两种主要并发症的机制相似。一个人类 APOC3 ASO已经在T2 DM患者中进行了测试，结果显示有希望降低TRL，因此APOC3 可能是抗击糖尿病并发症日益流行的治疗靶点。

A. SUMMARY OR ABSTRACT OF THE FUNDED PARENT GRANT OR PROJECT People with diabetes are more likely to have cardiovascular disease (CVD) and kidney disease. Most 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 (TRL) 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 APOC3 and a transcription factor (CREBH) that has profound effects selectively on TRL- 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.