APOC3 mediated dyslipidemia in diabetic kidney disease and atherosclerosis

A.获得资助的奖学金或项目摘要 糖尿病患者更容易患心血管疾病（CVD）和肾脏疾病。大部分 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 数据表明，载脂蛋白C3（APOC 3）在糖尿病动脉粥样硬化中起关键作用， 数据表明它与DKD有因果关系。APOC 3是富含磷脂酰肌醇脂蛋白（TRL）的关键调节因子 新陈代谢.它反过来又受胰岛素调节，但也受肾脏疾病调节。我们的总体假设是糖尿病 和肾脏疾病会提高APOC 3水平。TRL及其残余物的水平增加，由APOC 3驱动， 加速糖尿病肾病以及动脉粥样硬化。该假设将在2个单独的 目的：目的1：阻断APOC 3能预防糖尿病肾病吗？这将在两个不同的测试中进行测试 使用2种不同方法靶向APOC 3的糖尿病和肾脏疾病小鼠模型; 反义（阿索）的APOC 3和转录因子（CREBH），具有深远的影响，选择性地对TRL- 相关APOC 3。目的2：肾损害和糖尿病是否协同作用以升高APOC 3， 会导致动脉粥样硬化吗为了验证糖尿病和肾功能下降 协同地升高血浆APOC 3以加速动脉粥样硬化，我们将在非动脉粥样硬化患者中诱导肾损害， 糖尿病小鼠和糖尿病小鼠。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。

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.