title: Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes.
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.
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; dana.thomasova@med.uni-muenchen.de.
authors.forename: Dana
authors.initials: D
authors.lastname: Thomasova
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany;
authors.forename: Hauke A
authors.initials: HA
authors.lastname: Bruns
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany;
authors.forename: Victoria
authors.initials: V
authors.lastname: Kretschmer
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany;
authors.forename: Martrez
authors.initials: M
authors.lastname: Ebrahim
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany;
authors.forename: Simone
authors.initials: S
authors.lastname: Romoli
authors.affiliation: Pathology, Immunology, and Internal Medicine (Renal), School of Medicine, Washington University, St. Louis, Missouri;
authors.forename: Helen
authors.initials: H
authors.lastname: Liapis
authors.affiliation: Institut für Anatomie und Zellbiologie, Universitätsmedizin Greifswald, Greifswald, Germany; and|Department of Anatomy and Histology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Kotb
authors.affiliation: Institut für Anatomie und Zellbiologie, Universitätsmedizin Greifswald, Greifswald, Germany; and
authors.forename: Nicole
authors.initials: N
authors.lastname: Endlich
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany;
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D015153:Blotting, Western; D016923:Cell Death / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016158:Genes, p53 / Q000235:genetics / Q000502:physiology*; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006706:Homeostasis / Q000235:genetics; D007150:Immunohistochemistry; D007677:Kidney Function Tests; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D050199:Podocytes / Q000166:cytology / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D015533:Transcriptional Activation / Q000235:genetics* / Q000502:physiology; D015027:Zebrafish
chemical_list: C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
keywords: FSGS; autophagy; homeostasis; nephrotic syndrome; regulated necrosis