Mechanism of valproic acid‐induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney

Nephrology - Tập 23 Số 4 - Trang 351-361 - 2018
Reza Heidari1, Faezeh Jafari2, Forouzan Khodaei2, Babak Shirazi Yeganeh3, Hossein Niknahad2,1
1Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
3Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

Tóm tắt

AbstractAimDrug‐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.MethodsAnimals 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.ResultsValproic 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.ConclusionsThese 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.

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Nephrology

Tập 23 Số 4

351-361

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