Therapeutic activity of the histone deacetylase inhibitor SB939 on renal fibrosis

• Published in: International immunopharmacology 2017-01, Vol.42, p.25-31
• Main Authors: Kang, Sun-Woo, Lee, Soung-Min, Kim, Joo-Yong, Kim, So-Yeon, Kim, Yeong-Hoon, Kim, Tae-Hee, Kang, Mi-Seon, Jang, Won-Hee, Seo, Su-Kil
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Actin; AKT protein; Animals; Anti-Inflammatory Agents - therapeutic use; Benzimidazoles - therapeutic use; Cell Differentiation - drug effects; Cell Line; Cytokines; Cytotoxicity; Disease Models, Animal; Drugs; Fibrosis; HDAC inhibitor; Histone deacetylase; Histone Deacetylase Inhibitors - therapeutic use; Humans; Inflammation; Inhibitors; Kidney - drug effects; Kidney - pathology; Kidney diseases; Kidney Diseases - drug therapy; Kidney transplantation; MAP kinase; Medical treatment; Mesenchyme; Mice; Mice, Inbred C57BL; Myofibroblast; Myofibroblasts - drug effects; Myofibroblasts - physiology; Pharmacology; Rats; Renal fibrosis; Signal Transduction - drug effects; Smad protein; Smooth muscle; TGF-beta; Transforming Growth Factor beta - metabolism; Transforming growth factor-b1; Ureter; Ureteral Obstruction - drug therapy
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2016.11.008

Fibrosis is the final pathological outcome of many chronic kidney diseases and is quite common. Thus, development of effective anti-fibrotic agents is urgently needed. Although histone deacetylases (HDACs) have been reported to be involved in renal fibrosis, current HDAC inhibitors are unsatisfactory anti-fibrosis drugs. Therefore, more potentially relevant anti-renal fibrosis HDAC inhibitors are needed. We initially found that non-cytotoxic concentrations of SB939 (pracinostat) had strong anti-fibrotic activity, drastically decreasing TGF-β1-induced alpha smooth muscle actin (α-SMA) expression in the NRK renal fibroblast cell line. Similar anti-fibrotic activity of SB939 on epithelial-to-mesenchymal transition (EMT) was confirmed using the HK-2 human renal proximal tubular epithelial cell line. SB939 inhibited Smad-independent TGF-β signaling involving the MAPK and PI3K/AKT pathways. To evaluate in vivo anti-fibrotic activity, we administered SB939 in a unilateral ureteric obstruction (UUO) model. SB939 treatment markedly inhibited the accumulation of α-SMA and tissue injury. Inflammatory and pro-fibrotic cytokines in the obstructed kidney were also significantly decreased by SB939 treatment. Our results suggest that SB939 might be a promising therapeutic drug for preventing renal fibrosis. •Pan-HDAC inhibitor SB939 was investigated on renal fibrosis.•SB939 inhibits TGF-β1-induced myofibroblast generation.•SB939 inhibits Smad-independent pathways in TGF-β signaling.•Administration of SB939 into UUO model reduces renal fibrosis and inflammation.