title: MDM2 prevents spontaneous tubular epithelial cell death and acute kidney injury.
abstract: Murine double minute-2 (MDM2) is an E3-ubiquitin ligase and the main negative regulator of tumor suppressor gene p53. MDM2 has also a non-redundant function as a modulator of NF-kB signaling. As such it promotes proliferation and inflammation. MDM2 is highly expressed in the unchallenged tubular epithelial cells and we hypothesized that MDM2 is necessary for their survival and homeostasis. MDM2 knockdown by siRNA or by genetic depletion resulted in demise of tubular cells in vitro. This phenotype was completely rescued by concomitant knockdown of p53, thus suggesting p53 dependency. In vivo experiments in the zebrafish model demonstrated that the tubulus cells of the larvae undergo cell death after the knockdown of mdm2. Doxycycline-induced deletion of MDM2 in tubular cell-specific MDM2-knockout mice Pax8rtTa-cre; MDM2f/f caused acute kidney injury with increased plasma creatinine and blood urea nitrogen and sharp decline of glomerular filtration rate. Histological analysis showed massive swelling of renal tubular cells and later their loss and extensive tubular dilation, markedly in proximal tubules. Ultrastructural changes of tubular epithelial cells included swelling of the cytoplasm and mitochondria with the loss of cristae and their transformation in the vacuoles. The pathological phenotype of the tubular cell-specific MDM2-knockout mouse model was completely rescued by co-deletion of p53. Tubular epithelium compensates only partially for the cell loss caused by MDM2 depletion by proliferation of surviving tubular cells, with incomplete MDM2 deletion, but rather mesenchymal healing occurs. We conclude that MDM2 is a non-redundant survival factor for proximal tubular cells by protecting them from spontaneous p53 overexpression-related cell death.
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Munich, Germany.
authors.forename: Dana
authors.initials: D
authors.lastname: Thomasova
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Munich, Germany.
authors.forename: Martrez
authors.initials: M
authors.lastname: Ebrahim
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Munich, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Fleckinger
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Munich, Germany.
authors.forename: Moying
authors.initials: M
authors.lastname: Li
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Munich, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Molnar
authors.affiliation: Department of Anatomy and Cell Biology, Ludwig-Maximilians Universität, Munich, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Popper
authors.affiliation: Pathology & Immunology & Internal Medicine (Renal), Washington University, School of Medicine, St Louis, MO, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Liapis
authors.affiliation: Department of Anatomy and Cell Biology, Universitätsmedizin Greifswald, Greifswald, Germany.|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: Department of Anatomy and Cell Biology, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Siegerist
authors.affiliation: Department of Anatomy and Cell Biology, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Endlich
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Munich, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D007814:Larva; D018345:Mice, Knockout; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish
chemical_list: D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2