Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases

• Published in: The Journal of clinical investigation 2023-12, Vol.133 (24), p.1-18
• Main Authors: Tian, Xuefei, Pedigo, Christopher E, Li, Ke, Ma, Xiaotao, Bunda, Patricia, Pell, John, Lek, Angela, Gu, Jianlei, Zhang, Yan, Medina Rangel, Paulina X, Li, Wei, Schwartze, Eike, Nagata, Soichiro, Lerner, Gabriel, Perincheri, Sudhir, Priyadarshini, Anupama, Zhao, Hongyu, Lek, Monkol, Menon, Madhav C, Fu, Rongguo, Ishibe, Shuta
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Binding proteins; Biomedical research; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Death - genetics; Creatinine; Cytokinesis; Development and progression; DNA damage; DNA repair; Epithelial cells; Genotype & phenotype; Glomerulonephritis; Health aspects; Humans; Kidney diseases; Kidney Diseases - metabolism; Kidney Glomerulus - pathology; Mice; Mitosis; p53 Protein; Phenotypes; Physiological aspects; Podocytes - pathology; Prevention; Profilins - genetics; Proteins; Proteinuria; Proteinuria - pathology; Renal failure; Ribonucleic acid; Ribosomal DNA; Ribosomal RNA; RNA; RNA processing; RNA sequencing; rRNA; Scanning electron microscopy; Spindles; Tumor proteins
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI171237

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.