Abstract: FR-PO734
Podocyte Cell Cycle in Aging
Session Information
- Glomerular Diseases: Mechanisms and Podocyte Biology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Perin, Laura, Children's Hospital Los Angeles, Los Angeles, California, United States
- Hou, Xiaogang, Children's Hospital Los Angeles, Los Angeles, California, United States
- Villani, Valentina, Children's Hospital Los Angeles, Los Angeles, California, United States
- Dedhia, Charmi, Children's Hospital Los Angeles, Los Angeles, California, United States
- Aguiari, Paola, Children's Hospital Los Angeles, Los Angeles, California, United States
- De Filippo, Roger E., Children's Hospital Los Angeles, Los Angeles, California, United States
- Lemley, Kevin V., Children's Hospital Los Angeles, Los Angeles, California, United States
Background
Glomerulosclerosis is a prominent pathologic change of aging kidneys associated with hypertrophy and loss of podocytes. Podocytes are quiescent cells, but under a pathological state, they re-enter the cell cycle which promotes their loss when they cross the G1/S checkpoint. Here we study how the podocyte cell cycle phases change during aging in male vs female mice.
Methods
We established a FUCCI mouse (fluorescent ubiquitination-based cell cycle indicator) with fluorescent reporters exclusively in podocytes (Pod/FUCCI) to study cell cycle dynamics during aging in male and female mice. We analyzed n=8 males and n=12 females at 2-4m; n=17 males and n=15 females at 1 year, and n=29 males and n=24 females at 2 years of age. Podocytes were isolated by flow cytometry based on their cell cycle phase and podocyte loss was quantified by WT1 staining for all the time points. RNA seq was performed to study transcriptomics changes in podocytes at different cell cycle phases (G0 vs G1) at different ages.
Results
Podocyte number per glomerulus decreased during aging and podocyte loss was accompanied by an increase in glomerular size (hypertrophy) both in males and females. Flow cytometry results showed that in males, 92% of the podocytes at 4m were in G0 compared to 83% at 1 year and 81% at 2 years, while podocytes in the G1 phase increased from 4% at 4m to 12% and 17% at 1 year and 2 years, respectively. In female mice, 90% of podocytes were in G0 at 4m compared to 91% at 1 year and 79% at 2 years, 8% of the podocytes were in G0 at 4m compared to 3.5% and 17% at 1 year and 2 years, respectively. Sequencing results indicate that important molecular singling regulate the entrance in G1 phase, especially at later ages and that these signalings are different between males and females, highlighting the importance of sex differences related to the regulation of podocyte cell cycle phases.
Conclusion
Our data confirm, for the first time, that changes in podocyte cell cycle during aging differ between males and females, especially in relation to the G1 phase. Understanding the mechanisms that regulate cell cycle progression will help to identify new pathways that can be targeted to prevent podocyte loss and kidney disease accounting for sex differences.
Funding
- Private Foundation Support