Tempol, a Superoxide Dismutase Mimetic Agent, Ameliorates Cisplatin-Induced Nephrotoxicity through Alleviation of Mitochondrial Dysfunction in Mice

Abstract

BackgroundMitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice.Methods and FindingsNephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg) with or without oral administration of tempol (100 mg/kg/day). Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP) content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I–IV activities and mitochondrial nitric oxide synthase (mNOS) protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin-induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma.ConclusionThis study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction.

Effects of Single and Combined Losartan and Tempol Treatments on Oxidative Stress, Kidney Structure and Function in Spontaneously Hypertensive Rats with Early Course of Proteinuric Nephropathy

“…Earlier studies in the same experimental model also demonstrated that chronic losartan treatment improved kidney structure [3], while tempol effectively suppressed glomerular and tubular damage in various models of proteinuric nephropathy [10–12]. Here, Up/cr ratio showed higher positive correlation with glomerulosclerosis, than with an index of tubular damage, and was also in accordance with the MMP-1 protein expression.…”

Protective Effect of Tempol against Cisplatin-Induced Ototoxicity

“…The effect of co-administration of Tempol with cisplatin on the suppression of tumor growth in mice was similar to that observed in mice treated with cisplatin alone. Therefore, Tempol did not interfere with the anti-cancer effect of cisplatin against the growth of solid carcinomas [4]. …”

“…Tempol has been reported to restore the intracellular oxidative balance and reduce oxidative stress, resulting in alleviation of nephrotoxicity in mice [4], and reduced infarct size in rat and rabbit myocardial infarction models [5]. Moreover, it exerts a protective effect against lymphocyte genotoxicity [6].…”

Role of Rho Kinase Inhibition in the Protective Effect of Fasudil and Simvastatin Against 3-Nitropropionic Acid-Induced Striatal Neurodegeneration and Mitochondrial Dysfunction in Rats

“…Protein expression was assessed as previously described by Ahmed et al [30] using primary antibodies against peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and rho kinase 1 (ROCK1) from GeneTex, Inc. (Irvine, CA, USA) as well as phosphorylated-Akt (p-Akt), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), Bax, Bcl-2, and beta-actin (β-actin) from Thermo Fisher Scientific Inc. (Rockford, IL, USA). The amount of protein was quantified by densitometric analysis of the autoradiograms using a scanning laser densitometer (Biomed Instrument Inc., USA).…”