The inhibitory effect of chimeric decoy oligodeoxynucleotide against NF-κB and Sp1 in renal interstitial fibrosis

Abstract

The pathophysiology of chronic renal disease is characterized by a progressive loss of renal function and deposition of the extracellular matrix, leading to widespread tissue fibrosis. Much of the matrix in chronic renal disease is synthesized by interstitial myofibroblasts, recruited from resident fibroblasts and circulating precursors. These changes are believed to be derived from epithelial-mesenchymal transition (EMT) of tubuloepithelial cells. To develop a novel therapeutic approach for treating renal fibrosis, we examined the simultaneous inhibition of the transcription factors NF-κB and Sp1 in a mouse model of unilateral ureteral obstruction (UUO). To simultaneously inhibit both NF-κB and Sp1, we developed chimeric (Chi) decoy oligodeoxynucleotide (ODN) which contained binding sequences for both NF-κB and Sp1 in a single decoy molecule to enhance the effective use of decoy ODN strategy. Chi decoy ODN significantly attenuated tubulointerstitial fibrosis in a mouse model of UUO compared to scrambled decoy ODN, as demonstrated by the reduced interstitial volume, macrophage infiltration, and fibrosis-related gene expression. Interestingly, Chi decoy ODN also regulated EMT-related gene expression, leading to the inhibition of renal fibrotic changes in vivo and in vitro. The present study demonstrates the feasibility of Chi decoy ODN treatment for preventing renal fibrosis and EMT processes. This strategy might be useful to improve the clinical outcome after chronic renal disease.

Anti-fibrotic Effects of Synthetic Oligodeoxynucleotide for TGF-β1 and Smad in an Animal Model of Liver Cirrhosis

“…H&E, Masson’s Trichrome, and immunohistochemical staining were performed according to the described procedure 40 . Sections were stained with H&E and Masson’s Trichrome.…”

“…investigated that TGF-β type I receptor antisense ODN mediates knockdown of TGF-β1 signaling cascades. Kim et al 40 . found that chimeric decoy ODN affects renal interstitial fibrosis via the inhibition of both nuclear factor κB (NF-κB) and Sp1 transcription factors.…”

TNF-α stimulates endothelial palmitic acid transcytosis and promotes insulin resistance

“…Their sequences are as follows70: w-NF-κB-ODN 5 ′ -GAA ATT TCA GGG AAA TCC CTT CAA GAA AAC TTG AAG GGA TTT CCC T-3 ′ ; m-NF-κB-ODN, 5 ′ -GAA ATT TCA GGG AAA TTA CTT CAA GAA AAC TTG AAG TAA TTT CCC T-3 ′ . These ODN were annealed for 8 h, while the temperature decreased from 80 °C to 25 °C.…”

Small-Nucleic-Acid-Based Therapeutic Strategy Targeting the Transcription Factors Regulating the Vascular Inflammation, Remodeling and Fibrosis in Atherosclerosis

“…Several authors have demonstrated the feasibility of chimeric decoy ODN targeting simultaneously for NF-κB and E2F, NF-κB and E26 Ets, AP-, and Smad, NF-κB and Sp1, and Smad and Sp1 in inflammation and fibrotic lesions of various tissues [51,148,149,150,151,152,153]; it is expected that these results will extend to vascular fibrosis.…”