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National Institute of Environmental Health Sciences

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Publication Detail

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

Authors: Li, Li; Greene, Ilana; Readhead, Benjamin; Menon, Madhav C; Kidd, Brian A; Uzilov, Andrew V; Wei, Chengguo; Philippe, Nimrod; Schroppel, Bernd; He, John Cijiang; Chen, Rong; Dudley, Joel T; Murphy, Barbara

Published In Sci Rep, (2017 Jan 04)

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.

PubMed ID: 28051114 Exiting the NIEHS site

MeSH Terms: Allografts/pathology*; Animals; Cell Line; Computational Biology; Disease Models, Animal; Drug Discovery/methods; Fibrosis; Graft Rejection/drug therapy; Humans; Informatics; Kaempferols/administration & dosage*; Kidney Diseases/genetics; Kidney Diseases/pathology; Kidney Diseases/surgery; Kidney Transplantation/adverse effects*; Kidney/drug effects*; Kidney/pathology*; Male; Mice, Inbred BALB C; Signal Transduction/drug effects; Umbelliferones/administration & dosage*

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