title: 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.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 770 exington Ave., New York, NY 10065, USA.|Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Ilana
authors.initials: I
authors.lastname: Greene
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 770 exington Ave., New York, NY 10065, USA.|Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Readhead
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Madhav C
authors.initials: MC
authors.lastname: Menon
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 770 exington Ave., New York, NY 10065, USA.|Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kidd
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1255 5th Avenue, New York, NY 10029, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Uzilov
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Chengguo
authors.initials: C
authors.lastname: Wei
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Nimrod
authors.initials: N
authors.lastname: Philippe
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.|Section of Nephrology, University of Ulm, Albert-Einstein-Allee 23, Ulm, 89081 Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schroppel
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1255 5th Avenue, New York, NY 10029, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 770 exington Ave., New York, NY 10065, USA.|Department of Health Policy and Research, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA.|Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Murphy
mesh_terms: D064591:Allografts / Q000473:pathology*; D000818:Animals; D002460:Cell Line; D019295:Computational Biology; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000379:methods; D005355:Fibrosis; D006084:Graft Rejection / Q000188:drug therapy; D006801:Humans; D048088:Informatics; D044949:Kaempferols / Q000008:administration & dosage*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics / Q000473:pathology / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000187:drug effects; D014468:Umbelliferones / Q000008:administration & dosage*
chemical_list: D044949:Kaempferols; D014468:Umbelliferones; C006552:kaempferol; C007628:esculetin