title: Systems biology analysis reveals role of MDM2 in diabetic nephropathy.
abstract: To derive new insights in diabetic complications, we integrated publicly available human protein-protein interaction (PPI) networks with global metabolic networks using metabolomic data from patients with diabetic nephropathy. We focused on the participating proteins in the network that were computationally predicted to connect the urine metabolites.MDM2had the highest significant number of PPI connections. As validation, significant downregulation ofMDM2gene expression was found in both glomerular and tubulointerstitial compartments of kidney biopsy tissue from 2 independent cohorts of patients with diabetic nephropathy. In diabetic mice, chemical inhibition ofMDM2with Nutlin-3a led to reduction in the number of podocytes, increased blood urea nitrogen, and increased mortality. Addition of Nutlin-3a decreasedWT1+cells in embryonic kidneys. Both podocyte- and tubule-specificMDM2-knockout mice exhibited severe glomerular and tubular dysfunction, respectively. Interestingly, the only 2 metabolites that were reduced in both podocyte and tubule-specificMDM2-knockout mice were 3-methylcrotonylglycine and uracil, both of which were also reduced in human diabetic kidney disease. Thus, our bioinformatics tool combined with multi-omics studies identified an important functional role forMDM2in glomeruli and tubules of the diabetic nephropathic kidney and linksMDM2to a reduction in 2 key metabolite biomarkers.
authors: Institute of Metabolomic Medicine.|Center for Renal Translational Medicine, Division of Nephrology-Hypertension.|Division of Medical Genetics, Department of Medicine, UCSD, San Diego, California, USA.
authors: Rintaro
authors: R
authors: Saito
authors: Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU Munich, Munich, Germany.
authors: Anaïs
authors: A
authors: Rocanin-Arjo
authors: Center for Renal Translational Medicine, Division of Nephrology-Hypertension.|Division of Medical Genetics, Department of Medicine, UCSD, San Diego, California, USA.
authors: Young-Hyun
authors: YH
authors: You
authors: Institute of Metabolomic Medicine.|Division of Medical Genetics, Department of Medicine, UCSD, San Diego, California, USA.
authors: Manjula
authors: M
authors: Darshi
authors: Institute of Metabolomic Medicine.|Division of Medical Genetics, Department of Medicine, UCSD, San Diego, California, USA.
authors: Benjamin
authors: B
authors: Van Espen
authors: Center for Renal Translational Medicine, Division of Nephrology-Hypertension.|Division of Medical Genetics, Department of Medicine, UCSD, San Diego, California, USA.
authors: Satoshi
authors: S
authors: Miyamoto
authors: Center for Renal Translational Medicine, Division of Nephrology-Hypertension.|Division of Medical Genetics, Department of Medicine, UCSD, San Diego, California, USA.
authors: Jessica
authors: J
authors: Pham
authors: Institute of Metabolomic Medicine.|Department of Family Medicine and Epidemiology, UCSD, San Diego, California, USA.
authors: Minya
authors: M
authors: Pu
authors: Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU Munich, Munich, Germany.
authors: Simone
authors: S
authors: Romoli
authors: Institute of Metabolomic Medicine.|Department of Family Medicine and Epidemiology, UCSD, San Diego, California, USA.
authors: Loki
authors: L
authors: Natarajan
authors: Department of Internal Medicine, Nephrology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
authors: Wenjun
authors: W
authors: Ju
authors: Department of Internal Medicine, Nephrology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
authors: Matthias
authors: M
authors: Kretzler
authors: National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA.
authors: Robert
authors: R
authors: Nelson
authors: Division of Medical Genetics, Department of Medicine, UCSD, San Diego, California, USA.
authors: Keiichiro
authors: K
authors: Ono
authors: Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU Munich, Munich, Germany.
authors: Dana
authors: D
authors: Thomasova
authors: Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU Munich, Munich, Germany.
authors: Shrikant R
authors: SR
authors: Mulay
authors: Division of Medical Genetics, Department of Medicine, UCSD, San Diego, California, USA.
authors: Trey
authors: T
authors: Ideker
authors: Renal Pathology Laboratory, Columbia University, College of Physicians and Surgeons, Department of Pathology, New York, New York, USA.
authors: Vivette
authors: V
authors: D'Agati
authors: Salk Institute for Biological Studies, San Diego, California, USA.
authors: Ergin
authors: E
authors: Beyret
authors: Salk Institute for Biological Studies, San Diego, California, USA.
authors: Juan Carlos Izpisua
authors: JCI
authors: Belmonte
authors: Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU Munich, Munich, Germany.
authors: Hans Joachim
authors: HJ
authors: Anders
authors: Institute of Metabolomic Medicine.|Center for Renal Translational Medicine, Division of Nephrology-Hypertension.|Division of Medical Genetics, Department of Medicine, UCSD, San Diego, California, USA.|Veterans Affairs Health Systems, San Diego, California, USA.
authors: Kumar
authors: K
authors: Sharma
mesh_terms: D000419:Albuminuria; D000818:Animals; D019295:Computational Biology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D006801:Humans; D007678:Kidney Glomerulus / Q000503:physiopathology; D007684:Kidney Tubules / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D049490:Systems Biology
chemical_list: C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2