Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases.
Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases.
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Profilin1是预防小鼠和人类肾小球疾病有丝分裂突变所必需的。
DOI：
10.1172/jci171237
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发表时间：
2023-12-15
影响因子：
15.9
通讯作者：
Ishibe, Shuta
中科院分区：
文献类型：
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作者：
Tian, Xuefei;Pedigo, Christopher E.;Li, Ke;Ma, Xiaotao;Bunda, Patricia;Pell, John;Lek, Angela;Gu, Jianlei;Zhang, Yan;Rangel, Paulina X. Medina;Li, Wei;Schwartze, Eike;Nagata, Soichiro;Lerner, Gabriel;Perincheri, Sudhir;Priyadarshini, Anupama;Zhao, Hongyu;Lek, Monkol;Menon, Madhav C.;Fu, Rongguo;Ishibe, Shuta
蛋白尿性肾病的进展与足细胞丢失有关，但这一过程的机制尚不清楚。足细胞重新进入细胞周期以修复双链DNA断裂。然而，不成功的修复可导致足细胞穿过G1/S检查点并经历流产的胞质分裂。在这项研究中，我们确定Pfn 1是维持肾小球完整性不可或缺的-它在小鼠足细胞中的组织特异性损失导致严重的蛋白尿和肾衰竭。我们的研究结果表明，这种表型是由于足细胞有丝分裂灾难（MC），其特点是丰富的多核细胞，不规则的细胞核和有丝分裂纺锤体的组织学和超微结构。使用FUCCI 2aR小鼠鉴定足细胞细胞周期重入，我们观察到细胞周期相关蛋白的表达改变，如p21，p53，细胞周期蛋白B1和细胞周期蛋白D1。足细胞特异性翻译核糖体亲和纯化和RNA-Seq揭示了核糖体RNA加工8（Rrp 8）的下调。Rrp 8在Pfn 1-KO足细胞中的过表达在体外部分挽救了表型。对不同蛋白尿肾病患者的临床和超微结构断层扫描分析进一步证实了肾组织中MC足细胞的存在和足细胞PFN 1表达的减少。这些结果表明，profilin 1是必不可少的，在调节足细胞的细胞周期，其中断导致MC和随后的足细胞损失。
The progression of proteinuric kidney diseases is associated with podocyte loss, but the mechanisms underlying this process remain unclear. Podocytes reenter the cell cycle to repair double-stranded DNA breaks. However, unsuccessful repair can result in podocytes crossing the G1/S checkpoint and undergoing abortive cytokinesis. In this study, we identified Pfn1 as indispensable in maintaining glomerular integrity — its tissue-specific loss in mouse podocytes resulted in severe proteinuria and kidney failure. Our results suggest that this phenotype is due to podocyte mitotic catastrophe (MC), characterized histologically and ultrastructurally by abundant multinucleated cells, irregular nuclei, and mitotic spindles. Podocyte cell cycle reentry was identified using FUCCI2aR mice, and we observed altered expression of cell-cycle associated proteins, such as p21, p53, cyclin B1, and cyclin D1. Podocyte-specific translating ribosome affinity purification and RNA-Seq revealed the downregulation of ribosomal RNA-processing 8 (Rrp8). Overexpression of Rrp8 in Pfn1-KO podocytes partially rescued the phenotype in vitro. Clinical and ultrastructural tomographic analysis of patients with diverse proteinuric kidney diseases further validated the presence of MC podocytes and reduction in podocyte PFN1 expression within kidney tissues. These results suggest that profilin1 is essential in regulating the podocyte cell cycle and its disruption leads to MC and subsequent podocyte loss.
Terminator 小鼠是白喉毒素受体敲入小鼠品系，可快速有效地富集所需细胞谱系。
影响因子：
19.6
作者：
通讯作者：
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