Although chronic allograft damage (CAD) remains a primary barrier to long-term renal allograft survival, limited progress has been made in the discovery of potential therapeutics. In order to identify potential drug therapies, we used two meta-analytical methods to evaluate six post-renal transplant blood and biopsy gene expression data sets (N=275). This resulted in a list of 85 differentially expressed genes that were examined using the Connectivity Map Database (cMAP) in order to identify drugs with the capacity to interrupt the differential gene expression associated with CAD. Among the top ranking drugs, we identified kaempferol and esculetin as promising candidates, and we tested their therapeutic efficacy in a mouse unilateral ureteral obstruction (UUO) model and explored their putative mechanisms of action in renal tubular cells in vitro. Kaempferol and esculetin significantly decreased TGFβ and wnt mediated pro-fibrotic signaling and abrogated renal fibrosis in the UUO model, and in renal tubular cells in vitro. Therefore, kaempferol and esculetin represent potential novel anti-fibrotic agents in the treatment of CAD.
|Commitee:||Cijiang He, John, Tomer, Yaron|
|School:||Icahn School of Medicine at Mount Sinai|
|School Location:||United States -- New York|
|Source:||MAI 54/06M(E), Masters Abstracts International|
|Subjects:||Molecular biology, Medicine, Pharmacy sciences|
|Keywords:||Chronic allograft damage, Drug discovery, Nephrology, Transplantation|
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