title: Therapeutic activity of the histone deacetylase inhibitor SB939 on renal fibrosis.
abstract: 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.
authors.affiliation: Department of Nephrology, Busan Paik Hospital, College of Medicine, Inje University, Busan 614-735, South Korea.
authors.forename: Sun-Woo
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 614-735, South Korea.
authors.forename: Soung-Min
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Department of Orthopedic Surgery, Busan Korea Hospital, Busan 614-735, South Korea.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 614-735, South Korea.
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Nephrology, Busan Paik Hospital, College of Medicine, Inje University, Busan 614-735, South Korea.
authors.forename: Yeong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Nephrology, Busan Paik Hospital, College of Medicine, Inje University, Busan 614-735, South Korea.
authors.forename: Tae-Hee
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, Inje University, Busan 000-000, South Korea.
authors.forename: Mi-Seon
authors.initials: MS
authors.lastname: Kang
authors.affiliation: Department of Biochemistry, College of Medicine, Inje University, Busan 614-735, South Korea.
authors.forename: Won-Hee
authors.initials: WH
authors.lastname: Jang
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 614-735, South Korea. Electronic address: sseo@inje.ac.kr.
authors.forename: Su-Kil
authors.initials: SK
authors.lastname: Seo
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D005355:Fibrosis; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000188:drug therapy*
chemical_list: D000893:Anti-Inflammatory Agents; D001562:Benzimidazoles; D056572:Histone Deacetylase Inhibitors; C557525:SB939 compound; D016212:Transforming Growth Factor beta
keywords: HDAC inhibitor; Myofibroblast; Renal fibrosis; TGF-beta