title: Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney.
abstract: OBJECTIVE
  Drug-induced kidney proximal tubular injury and renal failure (Fanconi syndrome; FS) is a clinical complication. Valproic acid (VPA) is among the FS-inducing drugs. The current investigation was designed to evaluate the role of mitochondrial dysfunction and oxidative stress in VPA-induced renal injury.
  
  
  METHODS
  Animals received VPA (250 and 500 mg/kg, i.p., 15 consecutive days). Serum biomarkers of kidney injury and markers of oxidative stress were assessed. Moreover, kidney mitochondria were isolated and mitochondrial indices, including succinate dehydrogenase activity (SDA), mitochondrial depolarization, mitochondrial permeability transition pore (MPP), reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial glutathione, and ATP were determined.
  
  
  RESULTS
  Valproic acid-treated animals developed biochemical evidence of FS as judged by elevated serum gamma-glutamyl transferase (γ-GT), alkaline phosphatase (ALP), creatinine (Cr), and blood urea nitrogen (BUN) along with hypokalaemia, hypophosphataemia, and a decrease in serum uric acid. VPA caused an increase in kidney ROS and LPO. Renal GSH reservoirs were depleted and tissue antioxidant capacity decreased in VPA-treated animals. Renal tubular interstitial nephritis, tissue necrosis, and atrophy were also evident in VPA-treated rats. Mitochondrial parameters including SDA, MMP, GSH, ATP and MPP were decreased and mitochondrial ROS and LPO were increased with VPA treatment. It was found that carnitine (100 mg/kg, i.p.) mitigated VPA adverse effects towards the kidney.
  
  
  CONCLUSIONS
  These data suggest that mitochondrial dysfunction and oxidative stress contributed to the VPA-induced FS. On the other hand, carnitine could be considered a potentially safe and effective therapeutic option in attenuating VPA-induced renal injury.
authors.affiliation: Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Reza
authors.identifier: http://orcid.org/0000-0002-7038-9838
authors.initials: R
authors.lastname: Heidari
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Faezeh
authors.initials: F
authors.lastname: Jafari
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Forouzan
authors.initials: F
authors.lastname: Khodaei
authors.affiliation: Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Babak
authors.initials: B
authors.lastname: Shirazi Yeganeh
authors.affiliation: Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.|Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Niknahad
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001284:Atrophy; D004195:Disease Models, Animal; D005198:Fanconi Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009336:Necrosis; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014635:Valproic Acid
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D014635:Valproic Acid; D000255:Adenosine Triphosphate; D013385:Succinate Dehydrogenase; D005978:Glutathione
keywords: Fanconi syndrome; carnitine; energy metabolism; mitochondria; oxidative stress; renal injury