Abstract
Mequindox (MEQ), belonging to quinoxaline-di-N-oxides (QdNOs), is a synthetic antimicrobial agent widely used in China. Previous studies found that the kidney was one of the main toxic target organs of the QdNOs. However, the mechanisms underlying the kidney toxicity caused by QdNOs in vivo still remains unclear. The present study aimed to explore the molecular mechanism of kidney toxicity in mice after chronic exposure to MEQ. MEQ led to the oxidative stress, apoptosis, and mitochondrial damage in the kidney of mice. Meanwhile, MEQ upregulated Bax/Bcl-2 ratio, disrupted mitochondrial permeability transition pores, caused cytochrome c release, and a cascade activation of caspase, eventually induced apoptosis. The oxidative stress mediated by MEQ might led to mitochondria damage and apoptosis in a mitochondrial-dependent apoptotic pathway. Furthermore, upregulation of the Nrf2-Keap1 signaling pathway was also observed. Our findings revealed that the oxidative stress, mitochondrial dysfunction, and the Nrf2-Keap1 signaling pathway were associated with the kidney apoptosis induced by MEQ in vivo.
Highlights
Quinoxaline-di-N-oxides (QdNOs), consisting of one or two acyclic chain moiety combined with quinoxaline ring, are best known as potential antibacterial agents (Wu et al, 2007; Vicente et al, 2009; Wang et al, 2011a, 2015a, 2016c; Cheng et al, 2015; Liu et al, 2016, 2017)
We investigated comprehensively the following parameters: the effects of MEQ exposure on body and kidney weight, morphological and ultrastructural changes in kidney; activity of the uric acid (UA), urea, creatinine, blood urea nitrogen (BUN), GSH, total superoxide dismutase (T-SOD), MDA, 8-hydroxy deoxyguanosine (8-OHdG), and lactate dehydrogenase (LDH) in the serum; the mRNA expression of some genes in the kidney linked with apoptosis, and correlated with oxidative stress (e.g., Nrf-2, glutamate-cysteine ligase catalytic subunit (GCLC), NQO1, hydroxyl radicals (HO-1), glutathione peroxidase (GSH-Px), and glutathione S-transferase (GST)); the protein expression of cleaved caspase 3 and Nrf-2 in the kidney by immunohistochemistry, Western blot, and immunofluorescence assays
The coefficient of kidney to body weight was expressed as milligrams/(grams body weight, g)
Summary
Quinoxaline-di-N-oxides (QdNOs), consisting of one or two acyclic chain moiety combined with quinoxaline ring, are best known as potential antibacterial agents (Wu et al, 2007; Vicente et al, 2009; Wang et al, 2011a, 2015a, 2016c; Cheng et al, 2015; Liu et al, 2016, 2017). Carbadox (CBX), olaquindox (OLA), quinocetone (QCT), and cyadox (CYA) were the classical members of QdNOs (Wang et al, 2015a,b; Zhang et al, 2015). Mequindox (MEQ; 3-methyl-2-acetyl-N-1,4-dioxyquinoxaline, Abbreviations: 8-OHdG, 8-hydroxy deoxyguanosine; BUN, blood urea nitrogen; CBX, carbadox; crea, creatinine; CYA, cyadox; GCLC, glutamate-cysteine ligase catalytic subunit; GSH, glutathione; GSH-Px, glutathione peroxidase; GST, glutathione S-transferase; HO-1, hydroxyl radicals; IκB, nuclear factor κB protein; LDH, lactate dehydrogenase; M4, 3-methyl-2-(1-hydroxyethyl) quinoxaline-N4-monoxide; M8, 3-methyl-2-(1-hydroxyethyl) quinoxaline-N1-monoxide; MDA, malondialdehyde; MEQ, mequindox; N1-MEQ, N1-desoxymequindox; NQO1, NAD(P)H:quinoneoxidoreductase; OLA, olaquindox; QCT, quinocetone; QdNOs, quinoxaline-di-N-oxides; ROS, reactive oxygen species; SOD, superoxide dismutase; TEM, transmission electron microscope; T-SOD, total superoxide dismutase; UA, uric acid. As a synthetic antimicrobial agent, MEQ had significant antibacterial activities against both Gram-positive and Gram-negative species (Huang et al, 2015)
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