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JCI Insight. 2016 Oct 20;1(17):e87877. doi: 10.1172/jci.insight.87877.

Systems biology analysis reveals role of MDM2 in diabetic nephropathy.

Author information

1
Institute of Metabolomic Medicine.
2
Center for Renal Translational Medicine, Division of Nephrology-Hypertension.
3
Division of Medical Genetics, Department of Medicine, UCSD, San Diego, California, USA.
4
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU Munich, Munich, Germany.
5
Department of Family Medicine and Epidemiology, UCSD, San Diego, California, USA.
6
Department of Internal Medicine, Nephrology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
7
National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA.
8
Renal Pathology Laboratory, Columbia University, College of Physicians and Surgeons, Department of Pathology, New York, New York, USA.
9
Salk Institute for Biological Studies, San Diego, California, USA.
10
Veterans Affairs Health Systems, San Diego, California, USA.

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. MDM2 had the highest significant number of PPI connections. As validation, significant downregulation of MDM2 gene 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 of MDM2 with Nutlin-3a led to reduction in the number of podocytes, increased blood urea nitrogen, and increased mortality. Addition of Nutlin-3a decreased WT1+ cells in embryonic kidneys. Both podocyte- and tubule-specific MDM2-knockout mice exhibited severe glomerular and tubular dysfunction, respectively. Interestingly, the only 2 metabolites that were reduced in both podocyte and tubule-specific MDM2-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 for MDM2 in glomeruli and tubules of the diabetic nephropathic kidney and links MDM2 to a reduction in 2 key metabolite biomarkers.

PMID:
27777973
PMCID:
PMC5070958
DOI:
10.1172/jci.insight.87877
[Indexed for MEDLINE]
Free PMC Article

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