Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Metabolism. 2021 Jun;119:154740. doi: 10.1016/j.metabol.2021.154740. Epub 2021 Feb 25.
Apolipoprotein C3 (ApoC3) is a regulator of triglyceride metabolism and inflammation, and its plasma levels are positively correlated with the progression of diabetic nephropathy (DN) in patients. However, the role and underlying mechanism of ApoC3 in DN remain unclear.
Diabetes was induced in ApoC3 transgenic (Tg) and knockout (KO) mice by injection of streptozotocin. We studied the effect of ApoC3 on type 1 DN after 4 months of diabetes. Plasma glucose and lipid levels, renal function parameters and inflammation- and fibrogenesis-related gene and protein expression levels were studied. In vitro, human mesangial cells (HMCs) were incubated with high levels of glucose or/and triglyceride-rich lipoproteins (TRLs) with a high or low ApoC3 content isolated from Tg or wild-type (WT) mice, respectively, to explore the mechanisms of ApoC3 on development of DN.
We found that compared to WT mice, Tg mice exhibited hypertriglyceridemia (HTG), aggravated early renal function injury and inflammation, enlarged glomerular and mesangial surface areas, renal lipid deposition and elevated fibrogenesis-related gene expression levels after 4 months of diabetes. ApoC3 overexpression activated the renal Toll-like receptor 2 (TLR2) and nuclear factor-κB (NF-κB) signaling pathways and increased the renal gene and protein expression levels of the downstream inflammatory factors TNF-α, VCAM-1 and MCP-1. Unfortunately, we did not find that ApoC3 deficiency had an obvious protective effect against DN. In vitro, we found that TRLs with a high ApoC3 content increased the gene and protein expression levels of inflammation- and fibrogenesis-related factors in HMCs compared to those following administration of the same concentration of TRLs with a low ApoC3 content. These effects of ApoC3 were inhibited by blockade of TLR2 or NF-κB.
These findings suggest that ApoC3 aggravates early-stage DN by activating the renal TLR2/NF-κB pathway which is partially independent of HTG.
载脂蛋白 C3（ApoC3）是甘油三酯代谢和炎症的调节剂，其血浆水平与糖尿病肾病（DN）患者的进展呈正相关。然而，ApoC3 在 DN 中的作用及其潜在机制尚不清楚。
通过链脲佐菌素注射诱导 ApoC3 转基因（Tg）和敲除（KO）小鼠发生糖尿病。我们研究了 ApoC3 对 1 型 DN 的影响，研究时间为糖尿病发生后 4 个月。检测了血浆葡萄糖和脂质水平、肾功能参数以及炎症和纤维化相关基因和蛋白的表达水平。在体外，分别用高浓度葡萄糖或富含甘油三酯的脂蛋白（TRLs）孵育人肾小球系膜细胞（HMCs），这些 TRLs 分别来自 Tg 或野生型（WT）小鼠，且具有高或低 ApoC3 含量，以探讨 ApoC3 对 DN 发展的作用机制。
与 WT 小鼠相比，Tg 小鼠在糖尿病发生后 4 个月表现出高甘油三酯血症（HTG）、早期肾功能损伤和炎症加重、肾小球和系膜面积增大、肾脏脂质沉积和纤维化相关基因表达水平升高。ApoC3 过表达激活了肾脏 Toll 样受体 2（TLR2）和核因子-κB（NF-κB）信号通路，并增加了肾脏下游炎症因子 TNF-α、VCAM-1 和 MCP-1 的基因和蛋白表达水平。不幸的是，我们没有发现 ApoC3 缺乏对 DN 有明显的保护作用。在体外，我们发现与给予相同浓度低 ApoC3 含量的 TRLs 相比，高 ApoC3 含量的 TRLs 增加了 HMCs 中炎症和纤维化相关因子的基因和蛋白表达水平。这些 ApoC3 的作用可以通过阻断 TLR2 或 NF-κB 来抑制。
这些发现表明，ApoC3 通过激活肾脏 TLR2/NF-κB 通路加重早期 DN，该通路部分独立于 HTG。
