Project description:The role of endothelial dysfunction in tubulointerstitial fibrosis associated with chronic kidney disease (CKD) is not well understood. In this study, we demonstrate that the activation of the endothelial tyrosine kinase TIE2 alleviates renal pathology in experimental CKD in mice. TIE2 activation was achieved using a human angiopoietin-2 (ANGPT2)-binding and TIE2-activating antibody (ABTAA), or through adult-induced endothelial-specific knockout of the vascular endothelial protein tyrosine phosphatase gene (Veptp). Both methods significantly protected CKD mice from endothelial dysfunction, peritubular capillary loss, tubular epithelial injury, and tubulointerstitial fibrosis. Conversely, silencing TIE2 through adult-induced endothelial-specific knockout of the Tie2 gene exacerbated CKD pathology. Additionally, we found that endothelial dysfunction promotes renal fibrosis not through endothelial-to-mesenchymal transition as previously expected, but by inducing the expression of pro-fibrotic PDGFB in tubular epithelial cells, a process that is inhibited by TIE2 activation. Our findings suggest that TIE2 activation via ABTAA warrants investigation in human CKD, where there is a significant unmet medical need.
Project description:The mRNA transcriptome and m6A methylation microarray profiling of mouse kidney tissues. Kidney tissues from the sham-operated group and unilateral ureteral ligation/obstruction (UUO) kidney tissues were compared. The latter were mainly fibrotic kidney tissues. The goal was to identify the effect of the renal fibrosis on gene expression and corresponding m6A modifications during kidney fibrosis.
Project description:The mRNA transcriptome and m6A methylation microarray profiling of mouse kidney tissues. Kidney tissues from the sham-operated group and unilateral ureteral ligation/obstruction (UUO) kidney tissues were compared. The latter were mainly fibrotic kidney tissues. The goal was to identify the effect of the renal fibrosis on gene expression and corresponding m6A modifications during kidney fibrosis.
Project description:Animals were sc dosed with 5mg/kg anti-miR-214 or control anti-miR, had UUO performed and were sacrificed at 7 days. n=4 animals per group, 2 groups
Project description:Treatments for kidney fibrosis represent an urgent yet unmet clinical need. Effective therapies are limited due to not well understood molecular pathogenesis. We aimed at generating a comprehensive and integrated multi-omics data set (RNA/ microRNA transcriptomics and proteomics) of fibrotic kidneys which will be searchable through a user-friendly web application. Therefore, two commonly used mouse models were utilized: a reversible chemical-induced injury model (folic acid (FA) induced nephropathy) and an irreversible surgical-induced fibrosis model (unilateral ureteral obstruction (UUO)). RNA and small RNA sequencing as well as MS/MS with 10-plex tandem mass tags proteomics were performed with kidney samples from different time points over the course of fibrosis development. In summary, we present temporal and integrated multi-omics data from fibrotic mouse kidneys which are accessible through an interrogation tool to provide a searchable transcriptome and proteome for kidney fibrosis researcher.
Project description:RNA sequencing of sorted cell types, isolated from mice kidneys, after unilateral ureteral obstructive (UUO) surgery after 2 days, 7 days and a reversible (rUUO) 14 day model with corresponding sham operated mice. The goal of the study was to identify temporal gene expression changes in different cell types corresponding with kidney injury, in order to understand cell specific transcriptomic changes in the context of kidney injury and repair.
Project description:Label-free quantitative proteomics for mouse kidney tissue of UUO vs Sham was used for discovery of differential expressed proteins in the process of renal fibrosis. Compared to sham mice, we found that 216 upregulated proteins and 215 downregulated proteins in UUO mice according to fold change ≥ 5, adjusted-p ≤ 0.01. Then, we will study the potential mechanism according to differential expressed proteins.