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 4

Pharmacological inhibition of MDM2 in C57B6/JL healthy mice affects glomerular filtration barrier and kidney function.

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Pharmacological inhibition of MDM2 in C57B6/JL healthy mice affects glom...
(A) Survival of Nutlin-3a–treated mice (66% at the end of the study) compared with that of control mice (100%, P = 0.19, log-rank test). (B) Body weight monitoring along the treatment. While control mice increased progressively in weight, Nutlin-3a–treated mice lost weight progressively during the treatment, being significant from 18 weeks onwards compared with control mice. *P < 0.001, t test. Control, n = 9; Nutlin-3a, n = 9. (C) Albuminuria measured as urine albumin/creatinine ratio (ACR) along the study. ACR remained normal for control mice but increased progressively in Nutlin-3a–treated mice, being significantly higher at the end of the study. *P < 0.05, 1-tailed t test. Control, n = 7; Nutlin-3a treated, n = 7. (D) Blood urea nitrogen (BUN) levels at the end of the study were significantly higher in Nutlin-3a–treated mice compared with control mice. *P < 0.05, t test. Control group, n = 9; Nutlin-3a group, n = 7. Error bars represent standard errors (B and C). For box-and-whisker plots, the horizontal line in each box represents the median (D). The whiskers extend to 1.5 × (third quartile – first quartile).