title: Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis.
abstract: Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors.
authors.affiliation: Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium. kvbenede@vub.ac.be
authors.forename: Katrien
authors.initials: K
authors.lastname: Van Beneden
authors.forename: Caroline
authors.initials: C
authors.lastname: Geers
authors.forename: Marina
authors.initials: M
authors.lastname: Pauwels
authors.forename: Inge
authors.initials: I
authors.lastname: Mannaerts
authors.forename: Karl M
authors.initials: KM
authors.lastname: Wissing
authors.forename: Christiane
authors.initials: C
authors.lastname: Van den Branden
authors.forename: Leo A
authors.initials: LA
authors.lastname: van Grunsven
mesh_terms: D000107:Acetylation; D000818:Animals; D004317:Doxorubicin; D005260:Female; D005355:Fibrosis; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D020556:Neutrophil Infiltration; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; C012589:trichostatin A; D014635:Valproic Acid; D004317:Doxorubicin
keywords: Adriamycin; Glomerulosclerosis; Histone deacetylase; Proteinuria; Trichostatin A; Valproic acid