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Reno-protective effects of ursodeoxycholic acid against gentamicin-induced nephrotoxicity through modulation of NF-κB, eNOS and caspase-3 expressions

Abd-Elhamid, Tarek Hamdy, Elgamal, Dalia A., Ali, Safaa S., Ali, Fares E. M., Hassanein, Emad H. M., El-Shoura, Ehab A. M., Hemeida, Ramadan A. M.
Cell and tissue research 2018 v.374 no.2 pp. 367-387
B-lymphocytes, albumins, antioxidants, apoptosis, bacterial infections, blood serum, carboxymethylcellulose, caspase-3, creatinine, endothelial nitric oxide synthase, gentamicin, glutathione, immunohistochemistry, inflammation, kidneys, laboratory animals, males, malondialdehyde, messenger RNA, nephrotoxicity, oxidative stress, protective effect, rats, renal function, superoxide dismutase, tissues, transcription factor NF-kappa B, urea, uric acid, ursodeoxycholic acid
Gentamicin (GNT) is a potent aminoglycoside antibiotic widely used to treat life-threatening bacterial infections. We aim to investigate the potential protective effect of ursodeoxycholic acid (UDCA) against GNT-induced nephrotoxicity. In this study, 24 male Wistar rats were used and randomly divided into four groups of six animals each. Control group received 0.5% carboxymethyl cellulose orally for 15 days, GNT group received GNT 100 mg/kg/day i.p. for 8 days, UDCA group received UDCA orally for 15 consecutive days at a dose of 60 mg/kg/day suspended in 0.5% carboxymethyl cellulose and UDCA-pretreated group received UDCA orally for 7 days then co-administered with GNT i.p. for 8 days at the same fore-mentioned doses. Serum levels of kidney function parameters (urea, creatinine, uric acid and albumin) were measured. Renal tissues were used to evaluate oxidative stress markers; malonaldehyde (MDA), reduced glutathione (GSH) and the anti-oxidant enzyme superoxide dismutase (SOD) activities and nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and kidney injury molecule-1 (KIM-1) mRNA levels. Immunohistochemical expression of endothelial nitric oxide synthase (eNOS) and caspase-3 and histological and ultrastructural examination were performed. Treatment with GNT increased the serum levels of renal function parameters and renal MDA, NF-κB and KIM-1 mRNA levels, while it decreased GSH and SOD activities. Marked immunohistochemical expression of caspase-3 was observed after GNT administration while it decreased eNOS expression. Histological and ultrastructural alterations were also evident in renal corpuscles and tubules. In contrast, pretreatment with UDCA reversed changes caused by GNT administration. These results suggest that UDCA ameliorates GNT-induced kidney injury via inhibition of oxidative stress, inflammation and apoptosis.