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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. 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.

SUBMITTER: Saito R

PROVIDER: S-EPMC5070958 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Systems biology analysis reveals role of MDM2 in diabetic nephropathy.

Saito Rintaro R Rocanin-Arjo Anaïs A You Young-Hyun YH Darshi Manjula M Van Espen Benjamin B Miyamoto Satoshi S Pham Jessica J Pu Minya M Romoli Simone S Natarajan Loki L Ju Wenjun W Kretzler Matthias M Nelson Robert R Ono Keiichiro K Thomasova Dana D Mulay Shrikant R SR Ideker Trey T D'Agati Vivette V Beyret Ergin E Belmonte Juan Carlos Izpisua JCI Anders Hans Joachim HJ Sharma Kumar K

JCI insight 20161020 17

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. <i>MDM2</i> had the highest significant number of PPI connections. As validation, significant downregulation of <i>MDM2</i> gene expression was fou ...[more]

PMID: 27777973

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Systems biology analysis reveals role of MDM2 in diabetic nephropathy.

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Systems biology analysis reveals role of MDM2 in diabetic nephropathy.

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