Hydrogen sulfide (H2S) attenuates uranium-induced acute nephrotoxicity through oxidative stress and inflammatory response via Nrf2-NF-κB pathways

Jifang Zheng; Tingting Zhao; Yan Yuan; Nan Hu; Xiaoqing Tang

doi:10.1016/j.cbi.2015.10.021

Hydrogen sulfide (H2S) attenuates uranium-induced acute nephrotoxicity through oxidative stress and inflammatory response via Nrf2-NF-κB pathways

Chem Biol Interact. 2015 Dec 5:242:353-62. doi: 10.1016/j.cbi.2015.10.021. Epub 2015 Oct 31.

Authors

Jifang Zheng¹, Tingting Zhao¹, Yan Yuan¹, Nan Hu², Xiaoqing Tang³

Affiliations

¹ Institute of Biology, Pharmacy and Life College, University of South China, Changsheng West Road 28, Hengyang City, Hunan Province 421001, PR China.
² Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Changsheng West Road 28, Hengyang City, Hunan Province 421001, PR China.
³ Institute of Neuroscience, Medical College, University of South China, Changsheng West Road 28, Hengyang City, Hunan Province 421001, PR China. Electronic address: xiaoqingtang@outlook.com.

PMID: 26523793
DOI: 10.1016/j.cbi.2015.10.021

Abstract

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 μmol/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-κB 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 κB/p65, which decreased protein expression of target-p65 inflammatory genes TNF-α, 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-κB pathway.

Keywords: Hydrogen sulfide (H(2)S); NF-κB; Nephrotoxicity; Nrf2; Oxidative stress; Uranium.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Hydrogen Sulfide / metabolism*
Inflammation / metabolism
Kidney / cytology
Kidney / drug effects*
Kidney / metabolism*
Male
NF-E2-Related Factor 2 / metabolism*
NF-kappa B / metabolism*
Oxidative Stress / drug effects*
Rats
Rats, Sprague-Dawley
Uranium / toxicity*

Substances

NF-E2-Related Factor 2
NF-kappa B
Nfe2l2 protein, rat
Uranium
Hydrogen Sulfide