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Updated: Jul 13, 2025
An Efficient Sieving Method to Isolate Intact Glomeruli from Adult Rat Kidney
Published on: November 1, 2018
Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases
Xuefei Tian1, Christopher E Pedigo1, Ke Li2
1Section of Nephrology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
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.
Insights
Profilin1 (Pfn1) is crucial for maintaining podocyte health and kidney function. Its loss causes mitotic catastrophe, leading to severe kidney disease.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Biology
Background:
- Proteinuric kidney diseases involve podocyte loss, but mechanisms are unclear.
- Podocytes attempt DNA repair by reentering the cell cycle, but errors cause cell death.
- Mitotic catastrophe (MC) is a potential mechanism for podocyte loss in kidney disease.
Purpose of the Study:
- Investigate the role of Pfn1 in maintaining podocyte integrity.
- Determine if Pfn1 deficiency causes podocyte MC and kidney disease.
- Explore PFN1's role in human proteinuric kidney diseases.
Main Methods:
- Generated podocyte-specific Pfn1 knockout (KO) mice.
- Utilized FUCCI2aR mice to track podocyte cell cycle reentry.
- Performed RNA-Seq and ribosome profiling in Pfn1-KO podocytes.
- Analyzed kidney tissues from patients with proteinuric kidney diseases.
Main Results:
- Podocyte-specific Pfn1 loss caused severe proteinuria and kidney failure in mice.
- Histological and ultrastructural analysis revealed podocyte MC.
- Observed altered cell cycle protein expression (p21, p53, cyclin B1, cyclin D1).
- Downregulation of ribosomal RNA-processing 8 (Rrp8) was identified in Pfn1-KO podocytes.
- Overexpressing Rrp8 partially rescued Pfn1-KO podocyte phenotype in vitro.
- Confirmed MC podocytes and reduced PFN1 expression in human kidney disease tissues.
Conclusions:
- Profilin1 (Pfn1) is essential for regulating the podocyte cell cycle.
- Disruption of Pfn1 leads to podocyte mitotic catastrophe (MC).
- Pfn1 deficiency and MC contribute to podocyte loss and kidney disease progression.
- PFN1 may be a therapeutic target for proteinuric kidney diseases.
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