Division of Metabolism, Endocrinology, and Nutrition, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA.
VA Phoenix Health Care System, Phoenix, Arizona, USA.
JCI Insight. 2024 May 14;9(12):e177268. doi: 10.1172/jci.insight.177268.
Diabetes increases the risk of both cardiovascular disease and kidney disease. Notably, most of the excess cardiovascular risk in people with diabetes is in those with kidney disease. Apolipoprotein C3 (APOC3) is a key regulator of plasma triglycerides, and it has recently been suggested to play a role in both type 1 diabetes-accelerated atherosclerosis and kidney disease progression. To investigate if APOC3 plays a role in kidney disease in people with type 2 diabetes, we analyzed plasma levels of APOC3 from the Veterans Affairs Diabetes Trial. Elevated baseline APOC3 levels predicted a greater loss of renal function. To mechanistically test if APOC3 plays a role in diabetic kidney disease and associated atherosclerosis, we treated black and tan, brachyury, WT and leptin-deficient (OB; diabetic) mice, a model of type 2 diabetes, with an antisense oligonucleotide (ASO) to APOC3 or a control ASO, all in the setting of human-like dyslipidemia. Silencing APOC3 prevented diabetes-augmented albuminuria, renal glomerular hypertrophy, monocyte recruitment, and macrophage accumulation, partly driven by reduced ICAM1 expression. Furthermore, reduced levels of APOC3 suppressed atherosclerosis associated with diabetes. This suggests that targeting APOC3 might benefit both diabetes-accelerated atherosclerosis and kidney disease.
糖尿病增加了心血管疾病和肾脏疾病的风险。值得注意的是，糖尿病患者中大多数心血管疾病风险的增加都与肾脏疾病有关。载脂蛋白 C3（APOC3）是血浆甘油三酯的关键调节因子，最近有研究表明，APOC3 可能在 1 型糖尿病加速动脉粥样硬化和肾脏疾病进展中发挥作用。为了研究 APOC3 在 2 型糖尿病患者肾脏疾病中的作用，我们分析了退伍军人事务糖尿病试验中 APOC3 的血浆水平。基线时升高的 APOC3 水平预示着肾功能丧失更大。为了从机制上测试 APOC3 是否在糖尿病肾病和相关动脉粥样硬化中发挥作用，我们用 APOC3 的反义寡核苷酸（ASO）或对照 ASO 治疗黑褐、短吻鳄、WT 和瘦素缺乏（OB；糖尿病）小鼠，这是 2 型糖尿病的模型，同时还存在类似人类的血脂异常。沉默 APOC3 可预防糖尿病引起的白蛋白尿、肾脏肾小球肥大、单核细胞募集和巨噬细胞积累，这部分是由 ICAM1 表达减少驱动的。此外，APOC3 水平降低可抑制与糖尿病相关的动脉粥样硬化。这表明靶向 APOC3 可能有益于糖尿病加速的动脉粥样硬化和肾脏疾病。
