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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.

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