Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach

Abstract

Chronic allograft damage, defined by interstitial fibrosis and tubular atrophy (IF/TA), is a leading cause of allograft failure. Few effective therapeutic options are available to prevent the progression of IF/TA. We applied a meta-analysis approach on IF/TA molecular datasets in Gene Expression Omnibus to identify a robust 85-gene signature, which was used for computational drug repurposing analysis. Among the top ranked compounds predicted to be therapeutic for IF/TA were azathioprine, a drug to prevent acute rejection in renal transplantation, and kaempferol and esculetin, two drugs not previously described to have efficacy for IF/TA. We experimentally validated the anti-fibrosis effects of kaempferol and esculetin using renal tubular cells in vitro and in vivo in a mouse Unilateral Ureteric Obstruction (UUO) model. Kaempferol significantly attenuated TGF-β1-mediated profibrotic pathways in vitro and in vivo, while esculetin significantly inhibited Wnt/β-catenin pathway in vitro and in vivo. Histology confirmed significantly abrogated fibrosis by kaempferol and esculetin in vivo. We developed an integrative computational framework to identify kaempferol and esculetin as putatively novel therapies for IF/TA and provided experimental evidence for their therapeutic activities in vitro and in vivo using preclinical models. The findings suggest that both drugs might serve as therapeutic options for IF/TA.

Integrative bioinformatics identifies postnatal lead (Pb) exposure disrupts developmental cortical plasticity

“…Differential expression across the entire transcriptome was computed as the difference in rank between case and control (SubDiff), yielding a differential expression value ranging from −1 to +1. Code to generate these signatures was based on a microarray analysis pipeline built in-house 43 . To determine if genes shared by Pb and LPS exposure significantly overlapped, we first identified genes differentially expressed as those with a SubDiff Z-score of > 1.5 or <−1.5 (Pb 1125 genes, LPS 1485 genes).…”

Proteomics in Kidney Allograft Transplantation—Application of Molecular Pathway Analysis for Kidney Allograft Disease Phenotypic Biomarker Selection

“…We restricted our search to gene enrichment analyses in human renal biopsies and to studies describing pathways specific for AMR, TCMR, IFTA, and PVAN. As presented in Table , we identified two studies for AMR, five for TCMR, eight for IFTA, and two for PVAN using statistically validated differentially regulated gene expression and appropriate GO‐, IPA‐, and KEGG‐derived pathway mappings. To perform semantic clustering on these kidney transplantation related disease phenotypes by the software tool ReviGO, we converted IPA and KEGG pathways to GO biological processes using QuickGO, AmiGO, and UniProt.…”

An integrative systems biology approach for precision medicine in diabetic kidney disease

“…Integration of intrarenal transcriptomic data with patient‐specific non‐invasive molecular profile will allow generation of signatures that reflects individual's kidney progression pathogenesis. Pattern‐matching tools, which have been helpful in understanding disease and advancing the discovery of novel drugs in oncology can be applied to detect similarities among gene expression signatures . The drug‐specific molecular profile with the highest correlation to the patient's molecular profile is hypothesized to be the most appropriate candidate.…”

“…Pattern-matching tools, which have been helpful in understanding disease and advancing the discovery of novel drugs in oncology can be applied to detect similarities among gene expression signatures. [46][47][48][49] The drug-specific molecular profile with the highest correlation to the patient's molecular profile is hypothesized to be the most appropriate candidate. This type of integrative systems biology approach is "the right drug for the right patients" approach physician will need to advance treatment in DKD.…”