title: Sodium valproate ameliorates diabetes-induced fibrosis and renal damage by the inhibition of histone deacetylases in diabetic rat.
abstract: Recent reports emphasize the contribution of histone deacetylases (HDACs) in the pathogenesis of diabetic renal injury and fibrosis. Valproic acid (VPA) is a first-line drug used for the treatment of epilepsy and migraine as well as established as a HDAC inhibitor. The present study was aimed to evaluate the anti-fibrotic and renoprotective effects of VPA in diabetic nephropathy (DN). Diabetes was induced by single injection of STZ (50mg/kg), whereas VPA at the doses of 150 and 300mg/kg/day was administered for 8 consecutive weeks by oral route in Sprague Dawley rats. The renal injuries and fibrosis were assessed by histology, fibrosis specific staining and fibroblast activation by a transmission electron microscope, while expression of proteins of interest was evaluated by western blotting and immunohistochemistry. VPA treatment ameliorated the histological alterations as well as fibrosis, and decreased the expression of TGF-β1, CTGF, α-SMA, fibronectin, collagen I, COX-2, ICAM-1 and HDAC4/5/7. Further, VPA treatment significantly increased histone H3 acetylation and MMP-2 expression. The present study clearly established that VPA treatment ameliorates the renal injury and fibrosis in diabetic kidney by preventing the myofibroblast activation and fibrogenesis by HDAC inhibition and associated mechanisms, thereby improving the profibrotic and anti-fibrotic protein balance.
authors.affiliation: Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India. Electronic address: ksabbir25@gmail.com.
authors.forename: Sabbir
authors.initials: S
authors.lastname: Khan
authors.affiliation: Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India. Electronic address: gbjena@gmail.com.
authors.forename: Gopabandhu
authors.initials: G
authors.lastname: Jena
authors.affiliation: Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India. Electronic address: tikoo@niper.ac.in.
authors.forename: Kulbhushan
authors.initials: K
authors.lastname: Tikoo
mesh_terms: D000107:Acetylation / Q000187:drug effects; D058186:Acute Kidney Injury / Q000188:drug therapy; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D005355:Fibrosis / Q000188:drug therapy*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007668:Kidney / Q000293:injuries; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D013311:Streptozocin; D014635:Valproic Acid; D020778:Matrix Metalloproteinase 2; D006655:Histone Deacetylases
keywords: Diabetic nephropathy; HDAC inhibitor; Histone acetylation; Myofibroblast; Renal fibrosis; Sodium valproate; Transforming growth factor-beta 1