Systems biology analysis reveals role of MDM2 in diabetic nephropathy
Rintaro Saito, … , Hans Joachim Anders, Kumar Sharma
Rintaro Saito, … , Hans Joachim Anders, Kumar Sharma
Published October 20, 2016
Citation Information: JCI Insight. 2016;1(17):e87877. https://doi.org/10.1172/jci.insight.87877.
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Research Article Nephrology

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.

Authors

Rintaro Saito, Anaïs Rocanin-Arjo, Young-Hyun You, Manjula Darshi, Benjamin Van Espen, Satoshi Miyamoto, Jessica Pham, Minya Pu, Simone Romoli, Loki Natarajan, Wenjun Ju, Matthias Kretzler, Robert Nelson, Keiichiro Ono, Dana Thomasova, Shrikant R. Mulay, Trey Ideker, Vivette D’Agati, Ergin Beyret, Juan Carlos Izpisua Belmonte, Hans Joachim Anders, Kumar Sharma

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Figure 3

Expression levels of MDM2, HUWE1, PEX5, CUL4B, IFIT1, and TP53 in 2 independent data sets.

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Expression levels of MDM2, HUWE1, PEX5, CUL4B, IFIT1, and TP53 in 2 inde...
Data from European Renal cDNA Bank (ERCB) and Native Americans study (Pima) were used for the gene expression analyses. LD is control (living donor). (A) Expression data for MDM2. (B–E) Gene expression data from top bridge proteins (IFIT1, PEX5, HUWE1, and CUL4B) that came out of our network analysis are shown. Shown P values are uncorrected and based on t tests. For the top 5 bridge proteins, the P values that are significant (<0.05) after Bonferroni correction for multiple testing are marked with asterisks (*). (F) Expression data for TP53. The P values were significant (<0.05) after correction for multiple testing. Lower and upper edges of each box represents first and third quartiles of the distribution, respectively. The horizontal line in each box represents the median. The whiskers extend to 1.5 × (third quartile – first quartile). (G) Representative immunostaining of MDM2 in normal human kidney biopsy tissue (representative from n = 2) in upper panel and from a diabetic nephropathy biopsy tissue (representative from n = 3) in lower panel. Magnification, ×40.