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.

中文翻译：

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Profilin1 是预防小鼠和人类肾小球疾病有丝分裂灾难所必需的


蛋白尿肾病的进展与足细胞丢失有关，但这一过程的机制仍不清楚。足细胞重新进入细胞周期以修复双链 DNA 断裂。然而，不成功的修复可能导致足细胞穿过 G ₁ /S 检查点并经历流产的胞质分裂。在这项研究中，我们发现 Pfn1 对于维持肾小球完整性是不可或缺的——它在小鼠足细胞中的组织特异性缺失导致严重的蛋白尿和肾衰竭。我们的结果表明，这种表型是由于足细胞有丝分裂灾难（MC）造成的，其组织学和超微结构特征为丰富的多核细胞、不规则的细胞核和有丝分裂纺锤体。使用 FUCCI2aR 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（例如 p21、p53、细胞周期蛋白 B1 和细胞周期蛋白 D1）表达的改变。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 (Rrp8) 的下调。 Pfn1-KO 足细胞中 Rrp8 的过度表达部分挽救了体外表型。对患有多种蛋白尿肾病的患者进行的临床和超微结构断层扫描分析进一步证实了肾组织内 MC 足细胞的存在以及足细胞 PFN1 表达的减少。这些结果表明，profilin1 对于调节足细胞细胞周期至关重要，其破坏会导致 MC 和随后的足细胞损失。