PUBLICATION
Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes
- Authors
- Thomasova, D., Bruns, H.A., Kretschmer, V., Ebrahim, M., Romoli, S., Liapis, H., Kotb, A.M., Endlich, N., Anders, H.J.
- ID
- ZDB-PUB-141029-2
- Date
- 2015
- Source
- Journal of the American Society of Nephrology : JASN 26(7): 1513-23 (Journal)
- Registered Authors
- Keywords
- FSGS, autophagy, homeostasis, nephrotic syndrome, regulated necrosis
- MeSH Terms
-
- Analysis of Variance
- Animals
- Autophagy/genetics*
- Blotting, Western
- Cell Death/genetics*
- Cell Survival/genetics
- Cells, Cultured
- Disease Models, Animal
- Genes, p53/genetics
- Genes, p53/physiology*
- Glomerulosclerosis, Focal Segmental/genetics*
- Glomerulosclerosis, Focal Segmental/pathology
- Glomerulosclerosis, Focal Segmental/physiopathology
- Homeostasis/genetics
- Immunohistochemistry
- Kidney Function Tests
- Mice
- Mice, Knockout
- Microscopy, Confocal
- Podocytes/cytology
- Podocytes/physiology
- Proto-Oncogene Proteins c-mdm2/genetics*
- Real-Time Polymerase Chain Reaction/methods
- Sensitivity and Specificity
- Transcriptional Activation/genetics*
- Transcriptional Activation/physiology
- Zebrafish
- PubMed
- 25349197 Full text @ J. Am. Soc. Nephrol.
Citation
Thomasova, D., Bruns, H.A., Kretschmer, V., Ebrahim, M., Romoli, S., Liapis, H., Kotb, A.M., Endlich, N., Anders, H.J. (2015) Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes. Journal of the American Society of Nephrology : JASN. 26(7):1513-23.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping