N-acetylcysteine suppresses colistimethate sodium-induced nephrotoxicity via activation of SOD2, eNOS, and MMP3 protein expressions

Abstract

Objective: To investigate the molecular mechanisms of colistimethate sodium-induced nephrotoxicity and the protective effect of N-acetylcysteine (NAC) against nephrotoxicity.Methods: Twenty-eight Wistar rats were divided into four groups comprised of control, colistin, NAC, and colistin–NAC co-treatment, respectively. Serum creatinine and urine N-acetyl-β-d-glucosaminidase (NAG) levels were measured at different time intervals. Histological changes, apoptosis, total oxidant and antioxidant status, and the expression levels of endothelial nitric oxide synthase (eNOS), superoxide dismutase 2 (SOD2), and matrix metalloproteinase 3 (MMP3) were evaluated in renal tissue.Results: In the colistin group, post-treatment creatinine levels were higher than pretreatment levels (p = .001). There was a significant increase in urine NAG level following colistin treatment on day 10, compared to the baseline value and the first day of treatment (p = .001 and .0001, respectively). Urine NAG levels were higher in the colistin group on the 10th day of treatment than in the other groups (p < .01). Colistin treatment increased the apoptosis index and renal histological damage score (RHDS) significantly and these changes were reversed in NAC co-treatment (RHSD and apoptosis index were 45 and 0 for sterile saline group, 29 and 2 for NAC group, 122 and 7 for colistin group, and 66 and 2 for colistin + NAC group). We observed no difference between groups regarding total antioxidant and total oxidant status in the kidneys. The expression levels of eNOS, SOD2, and MMP3 decreased significantly in the kidneys of colistin-treated rats; these changes were reversed in the kidneys of NAC co-treated rats.Conclusions: N-acetylcysteine prevented colistin-induced nephrotoxicity through activation of expression levels of SOD2, eNOS, and MMP3.

Tempol improves redox status in mdx dystrophic diaphragm muscle

“…35 NAC was also able to promote overexpression of SOD2, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase 3 (MMP3) in rat kidneys. 36 In agreement with our results, previous studies also showed that tempol upregulated SOD2 activity and that this increase was accompanied by oxidative stress reduction. 37,38 Tempol can act by catalysing superoxide anion, promoting an increased hydroxyl radical (OH) level generation from hydrogen peroxide (H2O2).…”

Pharmacological agents for the prevention of colistin-induced nephrotoxicity

“…CMS for 10 days SCr, urine NAG, TOS, TAS, OSI, eNOS, SOD2, MMP, renal apoptosis (by TUNEL assay), renal histology examination Reversed colistin-induced negative effects, as determined by increased SCr, urine NAG, apoptosis index, and renal histological damage score as well as by decreased renal expression levels of eNOS, SOD2, and MMP [ 110 ] Silymarin Rats 50 mg/kg I.V silymarin twice a day 2 h before polymyxin E injection for 7 days A cumulative dose of 36.5 mg/kg I.V. polymyxin E given twice a day, 8 h apart, for 7 days Histological, ultrastructural, and morphometric changes Alleviated the degenerative changes on the rat kidney induced by polymyxin E [ 111 ] Silymarin Rats 50 mg/kg I.V silymarin twice a day 2 h before polymyxin E injection for 7 days A cumulative dose of 36.5 mg/kg I.V. polymyxin E given twice a day, 8 h apart, for 7 days SCr, serum urea, serum UA, serum Na, serum K, ameliorated the biochemical changes induced by polymyxin E in rats including elevated urinary NAG and serum levels of urea, creatinine, uric acid, sodium, and potassium.…”

“…However, no significant differences were observed between the study groups regarding the renal total antioxidant and oxidant capacity. Thus, the researchers proposed that NAC exerted its beneficial effects through the activation of SOD2 and eNOS expression levels as well as MMP3 [ 111 ].…”

Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity

“…Overall, the concomitant use of these agents with polymyxins has led to the reduced production of inflammatory and oxidative stress biomarkers [103,104,105,106]. Attenuation of both cellular apoptosis and histopathological changes in mice kidneys has been shown as well [103,105,107,108,109]. Nevertheless, not all studies have shown significant changes in serum creatinine values when comparing polymyxins prescribed alone or combined with anti-oxidant drugs [106,110], possibly because after a renal insult, there is a delay in the response of the serum creatinine concentration.…”