Abstract: FR-PO684
Cell Cycle and Senescence Regulation by Podocyte Histone Deacetylases 1 and 2
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1304 Glomerular Diseases: Podocyte Biology
Authors
- Medina Rangel, Paulina, Yale University, New Haven, Connecticut, United States
- Ishibe, Shuta, Yale University, New Haven, Connecticut, United States
Background
The loss of integrity of the glomerular filtration barrier results in proteinuria which is often attributed to the loss of podocytes. Despite the rising prevalence of proteinuric diseases, it is still unclear how podocytes are lost following damage. Senescence has been implicated to occur in age-related or by genomic stress such as DNA damage. Podocyte histone deacetylases (HDAC) are essential in maintaining a normal glomerular filtration barrier by modulating DNA-damage and preventing senescence.
Methods
Germline podocyte specific Hdac1 and 2 double knockout (DKO) mice were generated.
Results
Our research describes that podocyte-specific loss Hdac1 and 2 in mice results in severe proteinuria, collapsing glomerulopathy and sustained DNA damage, likely caused by deficient DNA damage repair in the absence of these enzymes. DNA damaged-podocytes not only re-entered the cell-cycle as studied with the FUCCI (Fluorescence-Ubiquitination-based Cell Cycle Indicator) system, but also exhibited p21-mediated cell-cycle arrest, which has been associated with cellular senescence. Consistent with these findings, podocyte senescence was demonstrated in vivo and in vitro by senescence-associated β-galactosidase activity and lipofuscin aggregates in the podocyte cell body. Through the senescence secretory associated phenotype, we evaluated that senescent podocytes secrete matrix metalloproteinases that may contribute to their detachment. Moreover, senescent podocytes were observed in the urine from these mutant mice.
Conclusion
Our findings suggest that Hdac1 and 2 are essential in podocytes development, as the deletion of these genes lead to sustained DNA damage, senescence and loss of podocytes. The role of HDACs in cell cycle regulation and senescence may provide important clues in our understanding of how podocytes are lost following injury.
Figure 1. Loss of podocyte Hdac1 and 2 in mice results in (A) collapsing glomerulopathy, (B) DNA damage (green) co-localized with WT-1 (red), (C) cell cycle re-entry, studied by FUCCI (WT-1 in blue, G1 phase in red) and (D) lipofuscin (blue granules), a marker of senescence.
Funding
- NIDDK Support