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Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes
Dana Thomasova1, Hauke A Bruns2, Victoria Kretschmer2
1Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; dana.thomasova@med.uni-muenchen.de.
Abstract:
Murine double minute-2 (MDM2), an E3 ligase that regulates the cell cycle and inflammation, is highly expressed in podocytes. In podocyte injury, MDM2 drives podocyte loss by mitotic catastrophe, but the function of MDM2 in resting podocytes has not been explored. Here, we investigated the effects of podocyte MDM2 deletion in vitro and in vivo. In vitro, MDM2 knockdown by siRNA caused increased expression of p53 and podocyte death, which was completely rescued by coknockdown of p53. Apoptosis, pyroptosis, pyronecrosis, necroptosis, ferroptosis, and parthanatos were excluded as modes of occurrence for this p53-overactivation-related cell death (here referred to as podoptosis). Podoptosis was associated with cytoplasmic vacuolization, endoplasmic reticulum stress, and dysregulated autophagy (previously described as paraptosis). MDM2 knockdown caused podocyte loss and proteinuria in a zebrafish model, which was consistent with the phenotype of podocyte-specific MDM2-knockout mice that also showed the aforementioned ultrastructual podocyte abnormalities before and during progressive glomerulosclerosis. The phenotype of both animal models was entirely rescued by codeletion of p53. We conclude that MDM2 maintains homeostasis and long-term survival in podocytes by preventing podoptosis, a p53-regulated form of cell death with unspecific features previously classified as paraptosis.
Insights
Murine double minute-2 (MDM2) protein is crucial for maintaining podocyte survival by preventing p53-induced cell death, termed podoptosis. Its absence leads to podocyte loss and kidney disease, highlighting MDM2
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Murine double minute-2 (MDM2) is an E3 ligase regulating cell cycle and inflammation, highly expressed in podocytes.
- While MDM2 drives podocyte loss in injury via mitotic catastrophe, its role in resting podocytes remains unclear.
Purpose of the Study:
- To investigate the function of MDM2 in resting podocytes by examining the effects of its deletion in vitro and in vivo.
- To elucidate the mechanism of p53-overactivation-related cell death in podocytes.
Main Methods:
- MDM2 knockdown using siRNA in vitro.
- MDM2 deletion in podocyte-specific knockout mice and zebrafish models.
- Assessment of cell death pathways, ultrastructural abnormalities, and kidney function (proteinuria, glomerulosclerosis).
Main Results:
- MDM2 knockdown in vitro increased p53 and caused podocyte death (podoptosis), rescued by p53 co-knockdown.
- Podoptosis involved cytoplasmic vacuolization, ER stress, and dysregulated autophagy, excluding other known cell death types.
- MDM2 deletion in mice and zebrafish models resulted in podocyte loss, proteinuria, and glomerulosclerosis, phenotypes fully rescued by p53 codeletion.
Conclusions:
- MDM2 is essential for maintaining podocyte homeostasis and survival by inhibiting p53-regulated cell death (podoptosis).
- Podoptosis is a distinct form of cell death characterized by specific ultrastructural and molecular features.
- Targeting MDM2 or p53 may offer therapeutic strategies for podocyte-related kidney diseases.
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