Novel therapeutics identification for fibrosis in renal allograft using integrative informatics approach

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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-ß1-mediated profibrotic pathways in vitro and in vivo, while esculetin significantly inhibited Wnt/ß-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.

Original languageEnglish (US)
Article number39487
JournalScientific Reports
Volume7
DOIs
StatePublished - Jan 4 2017
Externally publishedYes

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Informatics
Allografts
Fibrosis
Atrophy
Kidney
Therapeutics
Drug Repositioning
Pharmaceutical Preparations
Catenins
Wnt Signaling Pathway
Azathioprine
Kidney Transplantation
Meta-Analysis
Histology
kaempferol
esculetin
Gene Expression
In Vitro Techniques

ASJC Scopus subject areas

  • General

Cite this

Novel therapeutics identification for fibrosis in renal allograft using integrative informatics approach. / 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.

In: Scientific Reports, Vol. 7, 39487, 04.01.2017.

Research output: Contribution to journalArticle

Li, L, Greene, I, Readhead, B, Menon, MC, Kidd, BA, Uzilov, AV, Wei, C, Philippe, N, Schroppel, B, He, JC, Chen, R, Dudley, JT & Murphy, B 2017, 'Novel therapeutics identification for fibrosis in renal allograft using integrative informatics approach', Scientific Reports, vol. 7, 39487. https://doi.org/10.1038/srep39487
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. / Novel therapeutics identification for fibrosis in renal allograft using integrative informatics approach. In: Scientific Reports. 2017 ; Vol. 7.
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