Antifibrotic effect of synthetic Smad/Sp1 chimeric decoy oligodeoxynucleotide through the regulation of epithelial mesenchymal transition in unilateral ureteral obstruction model of mice

Abstract

Renal tubulointerstitial fibrosis is considered to be a common final pathway related to the progressive loss of renal function in chronic kidney disease. It is characterized by the excessive accumulation of extracellular matrix through the pivotal role of epithelial–mesenchymal transition. Transforming growth factor-β1 is postulated to play a central role in renal fibrosis via a downstream pathway such as Smad. Specificity protein 1 (Sp1), which is another transcription factor, is also involved in the basal expression of extracellular matrix. In this study, we investigate the effect of Smad decoy oligodeoxynucleotides (ODN) and Sp1 decoy ODN in unilateral ureteral obstruction induced renal fibrosis in mice. Furthermore, the effectiveness of the newly designed chimeric decoy ODN, which contains both Smad and Sp1 binding sequences in one decoy molecule (Smad/Sp1 chi decoy ODN), was demonstrated. The expression of fibrosis and inflammatory related cytokines and products of fibrosis were ameliorated in the Smad, Sp1 and chimeric decoy ODN treated groups compared with the scrambled decoy ODN treated group. Epithelial–mesenchymal transition was suppressed by the Smad, Sp1 and Smad/Sp1 chi decoy ODN. Immunohistochemistry and Western-blot analysis revealed that Smad/Sp1 chi decoy ODN showed a more significant inhibitory effect on fibrosis and EMT compared with Smad and Sp1 decoy ODNs. These results support the efficacy of Smad/Sp1 chi decoy compared with a single Smad or Sp1 decoy ODNs in preventing renal fibrosis induced by unilateral ureteral obstruction.