Departments of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Lab Invest. 2019 Jul;99(8):1107-1116. doi: 10.1038/s41374-019-0253-6. Epub 2019 Apr 24.
High-density lipoprotein (HDL) and its main protein, apolipoprotein AI (apoAI), have established benefits in various cells, but whether these cytoprotective effects of HDL pertain to renal cells is unclear. We investigated the in vitro consequences of exposing damaged podocytes to normal apoAI, HDL, and apoAI mimetic (L-4F), and the in vivo effects of L-4F on kidney and atherosclerotic injury in a podocyte-specific injury model of proteinuria. In vitro, primary mouse podocytes were injured by puromycin aminonucleoside (PAN). Cellular viability, migration, production of reactive oxygen species (ROS), apoptosis, and the underlying signaling pathway were assessed. In vivo, we used a proteinuric model, Nphs1-hCD25 transgenic (NEP25) mice, which express human CD25 on podocytes. Podocyte injury was induced by using immunotoxin (LMB2) and generated a proteinuric atherosclerosis model, NEP25:apoE mice, was generated by mating apoE-deficient (apoE) mice with NEP25 mice. Animals received L-4F or control vehicle. Renal function, podocyte injury, and atherosclerosis were assessed. PAN reduced podocyte viability, migration, and increased ROS production, all significantly lessened by apoAI, HDL, and L-4F. L-4F attenuated podocyte apoptosis and diminished PAN-induced inactivation of Janus family protein kinase-2/signal transducers and activators of transcription 3. In NEP25 mice, L-4F significantly lessened overall proteinuria, and preserved podocyte expression of synaptopodin and cell density. Proteinuric NEP25:apoE mice had more atherosclerosis than non-proteinuric apoE mice, and these lesions were significantly decreased by L-4F. Normal human apoAI, HDL, and apoAI mimetic protect against podocyte damage. ApoAI mimetic provides in vivo beneficial effects on podocytes that culminate in reduced albuminuria and atherosclerosis. The results suggest supplemental apoAI/apoAI mimetic may be a novel candidate to lessen podocyte damage and its complications.
高密度脂蛋白（HDL）及其主要蛋白载脂蛋白 AI（apoAI）在各种细胞中具有已确立的益处，但 HDL 的这些细胞保护作用是否与肾细胞有关尚不清楚。我们研究了将正常 apoAI、HDL 和 apoAI 模拟物（L-4F）暴露于受损足细胞的体外后果，以及 L-4F 在蛋白尿的足细胞特异性损伤模型中对肾脏和动脉粥样硬化损伤的体内影响。在体外，原代小鼠足细胞用嘌呤霉素氨基核苷（PAN）损伤。评估细胞活力、迁移、活性氧（ROS）产生、细胞凋亡和潜在的信号通路。在体内，我们使用了一种蛋白尿模型，Nphs1-hCD25 转基因（NEP25）小鼠，其在足细胞上表达人 CD25。使用免疫毒素（LMB2）诱导足细胞损伤，并产生了一种蛋白尿性动脉粥样硬化模型，NEP25：apoE 小鼠，是通过将 apoE 缺陷（apoE）小鼠与 NEP25 小鼠交配产生的。动物接受 L-4F 或对照载体。评估肾功能、足细胞损伤和动脉粥样硬化。PAN 降低了足细胞活力、迁移并增加了 ROS 产生，apoAI、HDL 和 L-4F 均显著减轻。L-4F 减轻了足细胞凋亡并减弱了 PAN 诱导的 Janus 家族蛋白激酶-2/信号转导和转录激活因子 3 的失活。在 NEP25 小鼠中，L-4F 显著减少了总蛋白尿，并维持了 synaptopodin 和细胞密度的足细胞表达。蛋白尿性 NEP25：apoE 小鼠的动脉粥样硬化比非蛋白尿性 apoE 小鼠多，L-4F 显著减少了这些病变。正常的人 apoAI、HDL 和 apoAI 模拟物可防止足细胞损伤。apoAI 模拟物为足细胞提供了有益的体内作用，最终减少了白蛋白尿和动脉粥样硬化。结果表明，补充 apoAI/apoAI 模拟物可能是减轻足细胞损伤及其并发症的一种新候选方法。
