Institute of Metabolomic Medicine.
Center for Renal Translational Medicine, Division of Nephrology-Hypertension.
JCI Insight. 2016 Oct 20;1(17):e87877. doi: 10.1172/jci.insight.87877.
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. had the highest significant number of PPI connections. As validation, significant downregulation of 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 with Nutlin-3a led to reduction in the number of podocytes, increased blood urea nitrogen, and increased mortality. Addition of Nutlin-3a decreased cells in embryonic kidneys. Both podocyte- and tubule-specific -knockout mice exhibited severe glomerular and tubular dysfunction, respectively. Interestingly, the only 2 metabolites that were reduced in both podocyte and tubule-specific -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 in glomeruli and tubules of the diabetic nephropathic kidney and links to a reduction in 2 key metabolite biomarkers.
为了深入了解糖尿病并发症，我们将公开的人类蛋白质-蛋白质相互作用（PPI）网络与使用糖尿病肾病患者代谢组学数据的全球代谢网络整合在一起。我们专注于网络中计算预测与尿液代谢物相关的参与蛋白。 在网络中具有最高数量的 PPI 连接。作为验证，在来自 2 个独立的糖尿病肾病患者队列的肾活检组织的肾小球和肾小管间质区室中均发现 基因表达显著下调。在糖尿病小鼠中，用 Nutlin-3a 化学抑制 导致足细胞数量减少、血尿素氮增加和死亡率增加。Nutlin-3a 的添加减少了胚胎肾脏中的 细胞。足细胞和肾小管特异性 -敲除小鼠分别表现出严重的肾小球和肾小管功能障碍。有趣的是，在足细胞和肾小管特异性 -敲除小鼠中均减少的两种代谢产物是 3-甲基戊烯二酸和尿嘧啶，它们在人类糖尿病肾病中也减少。因此，我们的生物信息学工具与多组学研究相结合，确定了 在糖尿病肾病肾脏的肾小球和肾小管中的重要功能作用，并将 与 2 种关键代谢物生物标志物的减少联系起来。
