Center for Kidney Disease and.
Department of Clinical Genetics, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
JCI Insight. 2021 Oct 8;6(19):e147716. doi: 10.1172/jci.insight.147716.
The role and mechanisms for upregulating complement factor B (CFB) expression in podocyte dysfunction in diabetic kidney disease (DKD) are not fully understood. Here, analyzing Gene Expression Omnibus GSE30528 data, we identified genes enriched in mTORC1 signaling, CFB, and complement alternative pathways in podocytes from patients with DKD. In mouse models, podocyte mTOR complex 1 (mTORC1) signaling activation was induced, while blockade of mTORC1 signaling reduced CFB upregulation, alternative complement pathway activation, and podocyte injury in the glomeruli. Knocking down CFB remarkably alleviated alternative complement pathway activation and DKD in diabetic mice. In cultured podocytes, high glucose treatment activated mTORC1 signaling, stimulated STAT1 phosphorylation, and upregulated CFB expression, while blockade of mTORC1 or STAT1 signaling abolished high glucose-upregulated CFB expression. Additionally, high glucose levels downregulated protein phosphatase 2Acα (PP2Acα) expression, while PP2Acα deficiency enhanced high glucose-induced mTORC1/STAT1 activation, CFB induction, and podocyte injury. Taken together, these findings uncover a mechanism by which CFB mediates podocyte injury in DKD.
在糖尿病肾病（DKD）中，足细胞功能障碍中补体因子 B（CFB）表达上调的作用和机制尚不完全清楚。在这里，通过分析基因表达综合数据库 GSE30528 数据，我们鉴定了 DKD 患者足细胞中富含 mTORC1 信号、CFB 和补体替代途径的基因。在小鼠模型中，诱导足细胞 mTOR 复合物 1（mTORC1）信号激活，而阻断 mTORC1 信号可减少 CFB 的上调、替代补体途径的激活以及肾小球中的足细胞损伤。敲低 CFB 可显著减轻糖尿病小鼠中替代补体途径的激活和 DKD。在培养的足细胞中，高葡萄糖处理激活 mTORC1 信号，刺激 STAT1 磷酸化，并上调 CFB 表达，而阻断 mTORC1 或 STAT1 信号可消除高葡萄糖上调的 CFB 表达。此外，高葡萄糖水平下调蛋白磷酸酶 2Acα（PP2Acα）的表达，而 PP2Acα 缺乏增强高葡萄糖诱导的 mTORC1/STAT1 激活、CFB 诱导和足细胞损伤。总之，这些发现揭示了 CFB 介导 DKD 中足细胞损伤的一种机制。
