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Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach
Li Li1,2, Ilana Greene3, Benjamin Readhead1,2
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 770 exington Ave., New York, NY 10065, USA.
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.
Insights
New research identifies kaempferol and esculetin as potential treatments for chronic allograft damage (IF/TA). These compounds showed anti-fibrotic effects in preclinical models, offering hope for preventing allograft failure.
Area of Science:
- Nephrology
- Pharmacology
- Computational Biology
Background:
- Chronic allograft damage, characterized by interstitial fibrosis and tubular atrophy (IF/TA), is a major cause of kidney transplant failure.
- Limited therapeutic options exist to prevent IF/TA progression.
Purpose of the Study:
- To identify novel therapeutic agents for IF/TA using a computational drug repurposing approach.
- To experimentally validate the efficacy of identified compounds in preclinical models.
Main Methods:
- Meta-analysis of IF/TA molecular datasets from the Gene Expression Omnibus database.
- Identification of an 85-gene signature for computational drug repurposing.
- In vitro validation using renal tubular cells and in vivo validation in a mouse Unilateral Ureteric Obstruction (UUO) model.
Main Results:
- An 85-gene signature for IF/TA was identified.
- Kaempferol and esculetin were computationally predicted as potential IF/TA therapies.
- Kaempferol attenuated TGF-β1 pathways; esculetin inhibited Wnt/β-catenin pathways.
- Both compounds demonstrated significant anti-fibrotic effects in vitro and in vivo.
Conclusions:
- Kaempferol and esculetin show promise as novel therapeutic options for IF/TA.
- An integrative computational framework can identify potential drug repurposing candidates for IF/TA.
