Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 242, Issue -, Pages 353-362Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2015.10.021
Keywords
Hydrogen sulfide (H2S); Uranium; Nephrotoxicity; Oxidative stress; Nrf2; NF-kappa B
Funding
- Natural Science Foundation of Hunan Province [14JJ2087]
- National Natural Science Foundation of China [81071005]
- Natural Science Innovation Foundation for Postgraduate Students in University of South China [CX2013B394]
- Defense Industrial Technology Development Program [B3720132001]
- Zhengxiang Scholar Program of University of South China [2014-004]
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As an endogenous gaseous mediator, H2S exerts anti-oxidative, anti-inflammatory and cytoprotective effects in kidneys. This study was designed to investigate the protective effect of H2S against uranium-induced nephrotoxicity in adult SD male rats after in vivo effect of uranium on endogenous H2S formation was explored in kidneys. The levels of endogenous H2S and H2S-producing enzymes (CBS and CSE) were measured in renal homogenates from rats intoxicated by an intraperitoneally (i.p.) injection of uranyl acetate at a single dose of 2.5, 5 or 10 mg/kg. In rats injected i.p. with uranyl acetate (5 mg/kg) or NaHS (an H2S donor, 28 or 56 mu mol/kg) alone or in combination, we determined biochemical parameters and histopathological alteration to assess kidney function, examined oxidative stress markers, and investigated Nrf2 and NF-kappa B pathways in kidney homogenates. The results suggest that uranium intoxication in rats decreased endogenous H2S generation as well as CBS and CSE protein expression. NaHS administration in uranium-intoxicated rats ameliorated the renal biochemical indices and histopathological effects, lowered MDA accumulation, and restored GSH level and anti-oxidative enzymes activities like SOD, CAT, GPx and GST. NaHS treatment in uranium-intoxicated rats activated uranium-inhibited protein expression and nuclear translocation of transcription factor Nrf2, which increased protein expression of downstream target-Nrf2 genes HO-1, NQO-1, GCLC, and TXNRD-1. NaHS administration in uranium-intoxicated rats inhibited uranium-induced nuclear translocation and phosphorylation of transcription factor kappa B/p65, which decreased protein expression of target-p65 inflammatory genes TNF-alpha, iNOS, and COX-2. Taken together, these data implicate that H2S can afford protection to rat kidneys against uranium-induced adverse effects through induction of antioxidant defense by activating Nrf2 pathway and reduction of inflammatory response by suppressing NF-kappa B pathway. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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