足细胞凋亡在糖尿病肾病中的作用：BASP1 通过 WT1 激活 p53 通路。
Podocyte apoptosis in diabetic nephropathy by BASP1 activation of the p53 pathway via WT1.
机构信息
Department of Nephrology, The Children Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, China.
Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
出版信息
Acta Physiol (Oxf). 2021 May;232(1):e13634. doi: 10.1111/apha.13634. Epub 2021 Mar 14.
AIMS
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. BASP1 (brain acid-soluble protein) is up-regulated in podocyte-specific protein phosphatase 2A knockout mice (Pod-PP2A-KO) that develop kidney dysfunction. Here, we explore the role of BASP1 for podocytes in DN.
METHODS
BASP1 was assessed in kidneys from DN patients and DN mouse models, podocyte specific BASP1 knockout mice (Pod-BASP1-KO mice) were generated and studied in vivo. Furthermore, podocyte injury and apoptosis were measured after BASP1 knockdown and overexpression in a mouse podocyte cell line (MPC5). Potential signalling pathways involved in podocyte apoptosis were detected.
RESULTS
BASP1 expression was up-regulated in DN patients compared to normal controls. BASP1 specific deletion in podocytes protected against podocyte injury by reducing the loss of expression of slit diaphragm molecules and foot process effacement in the DN model. BASP1 promoted actin cytoskeleton rearrangements and apoptosis in the MPC5 podocyte line. Molecules involved in the p53 pathway were down-regulated in BASP1 knockdown podocytes treated with high glucose compared to controls. BASP1 promoted podocyte apoptosis and P53 pathway activation through co-repression with Wilms' tumour 1 transcription factor (WT1).
CONCLUSION
BASP1 activates the p53 pathway through modulation of WT1 to induce podocyte apoptosis in diabetic nephropathy.
目的
糖尿病肾病（DN）是终末期肾病的主要原因。脑酸性可溶性蛋白 1（BASP1）在出现肾功能障碍的足细胞特异性蛋白磷酸酶 2A 敲除小鼠（Pod-PP2A-KO）中上调。在这里，我们探讨了 BASP1 在 DN 足细胞中的作用。
方法
在 DN 患者和 DN 小鼠模型的肾脏中评估 BASP1 的表达，生成并研究足细胞特异性 BASP1 敲除小鼠（Pod-BASP1-KO 小鼠）。此外，在小鼠足细胞系（MPC5）中敲低和过表达 BASP1 后测量足细胞损伤和凋亡。检测涉及足细胞凋亡的潜在信号通路。
结果
与正常对照组相比，DN 患者的 BASP1 表达上调。BASP1 在足细胞中的特异性缺失可通过减少 DN 模型中裂孔隔膜分子的表达损失和足突融合来防止足细胞损伤。BASP1 可促进 MPC5 足细胞系中肌动蛋白细胞骨架重排和细胞凋亡。与对照组相比，在高糖处理的 BASP1 敲低足细胞中，p53 通路相关分子下调。BASP1 通过与维尔姆斯瘤 1 转录因子（WT1）共同抑制来促进足细胞凋亡和 p53 通路激活。
结论
BASP1 通过调节 WT1 激活 p53 通路，在糖尿病肾病中诱导足细胞凋亡。
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