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Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases
Xuefei Tian, … , Rongguo Fu, Shuta Ishibe
Xuefei Tian, … , Rongguo Fu, Shuta Ishibe
Published October 17, 2023
Citation Information: J Clin Invest. 2023;133(24):e171237. https://doi.org/10.1172/JCI171237.
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Research Article Cell biology Nephrology

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

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Abstract

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.

Authors

Xuefei Tian, Christopher E. Pedigo, Ke Li, Xiaotao Ma, Patricia Bunda, John Pell, Angela Lek, Jianlei Gu, Yan Zhang, Paulina X. Medina Rangel, Wei Li, Eike Schwartze, Soichiro Nagata, Gabriel Lerner, Sudhir Perincheri, Anupama Priyadarshini, Hongyu Zhao, Monkol Lek, Madhav C. Menon, Rongguo Fu, Shuta Ishibe

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Figure 7

Overexpression of Rrp8 mitigates DNA damage and improves MC appearance in Pfn1-KO podocytes.

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Overexpression of Rrp8 mitigates DNA damage and improves MC appearance i...
(A) Representative immunofluorescence images of podocytes in control and Pfn1-KO glomeruli at 5 weeks of age stained with Rrp8 (green) and WT1 (red). Scale bar: 20 μm. (B) Quantification of immunofluorescence intensity of Rrp8 per podocyte in A. Total of 320 podocytes in 6 different mice. (C) Representative immunofluorescence images of podocytes isolated from control and Pfn1-KO mice at P7 stained with Rrp8 (red) and Hoechst (blue). Scale bar: 20 μm. (D) Quantification of immunofluorescence intensity of Rrp8 per podocyte in C. Total of 320 podocytes in 5 independent experiments. (E and G) Representative immunofluorescence images of podocyte isolated from Pfn1-KO mouse at P7 transduced with mouse Rrp8 lentiviral activation particles or control particles (Ctrl), followed by staining with Rrp8 (red) and Hoechst (blue), as shown in E, or γH2AX (green) and WT1 (red), as shown in G. Scale bar: 20 μm. (F) Quantification of the percentage of MC podocytes per field of view in E. Total of 100 fields of view in 5 independent experiments. (H) Quantification of γH2AX foci per podocyte nucleus (left) and per podocyte nuclear area (right) in G. Total of 400 cells in 5 independent experiments. *P < 0.05 vs. control. Statistics were analyzed via a 2-tailed t test. OE, overexpression.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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