Exploration the potential mechanism of the SIRT1 and its target gene FOXO1/PPARGC1A in uteropelvic junction obstruction

BACKGROUND: Uteropelvic junction obstruction (UPJO) is a common surgical condition, which refers to the blockage of urine flowing through kidney into proximal upper ureter. However, the underlying mechanism of UPJO is poorly understood, especially the regulated and targeted genes of sirtuin 1 in UPJO. METHODS: We sequenced three renal tissues on the obstructed side of independent children with <20% differential renal function (DRF) and three samples with >40% DRF. Gene expression values were obtained and compared for differentially expressed genes (DEGs). Protein-protein interaction (PPI) analysis was conducted to identify the overlapping proteins of DEGs and Sirtuin 1 (SIRT1). The co-expression genes of overlapped genes were computed using Pearson correlation coefficient. The potential role of SIRT1 gene in UPJO was explored by resequencing 3 microarray data from RNA interference (RNAi) SIRT1 lines of renal tubular epithelial (NRK52E) cells in rat and three control datasets were sequenced again. The DEGs were obtained as parallel. GO/KEGG enrichment analysis and co-expression network were conducted to explore the underlying mechanism, particularly shared pathways or function in GO/KEGG enrichment analysis results. RESULTS: A total of 427 up-regulated genes and 1,099 down-regulated genes were identified among 3 mRNA-seq of renal tissue on the obstructed side of the independent children with <20% DRF and 3 samples with >40% DRF. According to prediction using the Search Tool for Retrieval of Interacting Genes/Proteins, 2 PPIs, FOXO1 and PPARGC1A, were identified among 2,524 DEGs, predicted as targets of SIRT1. Gene set enrichment analysis (GSEA) of their co-expression genes showed they may co-participate in biological activities including fatty acid degradation, regulation of signal transduction by p53 mediator. Moreover, GSEA results of DEGs was confirmed through RNAi SIRT1 lines of rat renal tubular epithelial (NRK52E) cells. CONCLUSIONS: UPJO may cause abnormal phenotypic changes of renal tubular epithelial cells through SIRT1/FOXO1 mediated protein transport, establishment of protein localization, and intracellular transport. In addition, UPJO is involved in regulation of signal transduction, regulation of intracellular estrogen receptor signaling pathways, and nucleoprotein localization through SIRT1/PPARGC1A-mediated p53 mediators, causing abnormal phenotypic changes in renal tubular epithelial cells.