Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Dec;52(6):622-630.
doi: 10.1097/SHK.0000000000001319.

N-Acetylcysteine Ameliorates Gentamicin-Induced Nephrotoxicity by Enhancing Autophagy and Reducing Oxidative Damage in Miniature Pigs

Jing Cui  1 , Li Tang, Quan Hong, Shupeng Lin, Xuefeng Sun, Guangyan Cai, Xue-Yuan Bai, Xiangmei Chen
Affiliations

N-Acetylcysteine Ameliorates Gentamicin-Induced Nephrotoxicity by Enhancing Autophagy and Reducing Oxidative Damage in Miniature Pigs

Jing Cui et al. Shock. 2019 Dec.

Abstract

The clinical use of gentamicin over prolonged periods is limited because of dose and time-dependent nephrotoxicity, in which intracellular oxidative stress and heightened inflammation have been implicated. Macroautophagy/autophagy is an essential and highly conserved self-digestion pathway that plays important roles in the maintenance of cellular function and viability under stress. The aim of this study was to determine changes in autophagy in response to the antioxidant N-acetylcysteine (NAC), via its effects on oxidative stress, inflammation, apoptosis, and renal function, following treatment with gentamicin in mini pigs. Adult mini pigs were divided into isotonic saline solution, gentamicin, and gentamicin plus NAC combination treatment groups. Gentamicin-induced histopathological changes, including inflammatory cell infiltration and tubular necrosis, were attenuated by NAC. NAC ameliorated the gentamicin-induced decreases in the levels of autophagy-related proteins, such as LC3 (microtubule-associated protein 1 light chain 3), PINK1 (phosphatase and tensin homologue deleted on chromosome10-induced kinase 1), phospho-parkin, AMBRA1 (activatingmolecule in Beclin 1-regulated autophagy), p62/SQSTM1 (sequestosome protein 1), and polyubiquitinated protein aggregates. NAC also caused a significant reduction in oxidative damage markers, including 4-hydroxy-2-nonenal, protein carbonyls, γ-H2AX (gamma histone variant H2AX), and 8-hydroxy-2'-deoxyguanosine, in gentamicin-treated animals. These data show that the protective effects of NAC might be related, at least in part, to a reduced inflammatory response, as observed in animals treated with both gentamicin and NAC. These results suggest that autophagy could be a new therapeutic target for preventing gentamicin-induced kidney injury, and that NAC might ameliorate gentamicin-induced nephrotoxicity by autophagy.

PubMed Disclaimer

Conflict of interest statement

The authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Effects of N-acetylcysteine on renal histology in gentamicin-induced AKI model mini pigs.
Fig. 2
Fig. 2
Effects of N-acetylcysteine on autophagy in the kidneys of gentamicin-induced AKI mini pigs.
Fig. 3
Fig. 3
Effects of N-acetylcysteine on oxidative damage in the kidneys of gentamicin-induced AKI mini pigs.
Fig. 4
Fig. 4
Transmission electron microscopy (TEM) images of mitochondrial structures in renal tissues of gentamicin-treated pigs.
Fig. 5
Fig. 5
Effects of N-acetylcysteine on apoptosis and the inflammatory response in gentamicin-injected AKI mini pigs.
See this image and copyright information in PMC

References

    1. Chawla LS, Kimmel PL. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int 82:516–524, 2012. - PubMed
    1. Johnson ST, Bigam DL, Emara M, Obaid L, Slack G, Korbutt G, Jewell LD, Van Aerde J, Cheung PY. N-acetylcysteine improves the hemodynamics and oxidative stress in hypoxic newborn pigs reoxygenated with 100% oxygen. Shock 28:484–490, 2007. - PubMed
    1. Kalghatgi S, Spina CS, Costello JC, Liesa M, Morones-Ramirez JR, Slomovic S, Molina A, Shirihai OS, Collins JJ. Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in mammalian cells. Sci Transl Med 5:192ra85, 2013. - PMC - PubMed
    1. Pyo CW, Shin N, Jung KI, Choi JH, Choi SY. Alteration of copper-zinc superoxide dismutase 1 expression by influenza A virus is correlated with virus replication. Biochem Biophys Res Commun 450:711–716, 2014. - PubMed
    1. Fowdar K, Chen H, He Z, Zhang J, Zhong X, Zhang J, Li M, Bai J. The effect of N-acetyl cysteine on exacerbations of chronic obstructive pulmonary disease: a meta-analysis and systematic review. Heart Lung 46:120–128, 2017. - PubMed

Publication types

MeSH terms