Abstract

Background: Gentamicin (GM) is an antibiotic that is widely used to treat many Gram-negative bacteria, such as those involved in urinary tract infections. However, being nephrotoxic, GM dose adjustment and reno-protective elements must be concurrently administered with GM to minimize kidney damage. Oxidative stress plays a pivotal role in the pathogenesis of GM-induced nephrotoxicity. Thymoquinone (TQ) is a promising therapeutic substance, that is being extensively studied in many diseases, such as diabetes mellitus, cancer, hypertension, and others. The powerful antioxidant properties of TQ may greatly help in minimizing GM nephrotoxicity. Metformin (MF) is a well-known, clinically approved oral hypoglycaemic drug that has many other actions, including antioxidant properties. The aim of this work was to evaluate the possible antioxidant and reno-protective effects of TQ and metformin in GM-induced nephrotoxicity in the same model (rats) at the same time. In addition, we aimed to further understand the effects underlying GM-induced nephrotoxicity. Methods: Twenty male rats were randomly divided into four equal groups: the first group (control) received distilled water; the second group received GM only; the third group received concurrent oral TQ and GM; and the fourth group received concurrent oral MF and GM. After 4 weeks, renal function and histopathology, as well as levels of the oxidative markers glutathione peroxidase-1 (GLPX1), superoxide dismutase (SOD), and malondialdehyde (MDA) in the kidney tissues, were assessed. Results: Compared with the control group, and as expected, the GM-injected rats showed significant biochemical and histological changes denoting renal damage. Compared with GM-injected rats, the concurrent administration of TQ with GM significantly reduced the levels of serum creatinine, serum urea, and tissue MDA and significantly increased the levels of GLPX1 and SOD. Concurrent metformin administration with GM significantly increased the levels of both GLPX1 and SOD and significantly decreased the levels of tissue MDA but had no significant effect on serum creatinine and urea levels. Compared with GM-injected rats, the addition of either TQ or MF resulted in a reduction in endothelial proliferation and mesangial hypercellularity. Conclusions: Both TQ and MF effectively alleviated the oxidative stress in GM-induced nephrotoxicity in rats, with TQ but not MF producing a complete reno-protective effect. Further studies for evaluation of different reno-protective mechanisms of TQ should be conducted.

Highlights

  • Antibiotics, especially aminoglycosides, have been notably linked to the development of nephrotoxicity that may end in acute kidney injury (AKI)

  • To confirm that our rat model accurately represented GM-induced nephrotoxicity, we first assessed renal function and markers of oxidative stress in rats that had been treated with GM daily for four weeks

  • Rats treated with GM showed both significant biochemical and histological changes when compared with the control group

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Summary

Introduction

Antibiotics, especially aminoglycosides, have been notably linked to the development of nephrotoxicity that may end in acute kidney injury (AKI). In 1980, Moir’ et al, proposed a central mechanism for the gentamicin-induced AKI that involved the accumulation of the drug in the lysosomes of the cells of the proximal tubule with subsequent inhibition of specific enzymes activities. Gentamicin-induced AKI had been attributed mainly to apoptosis of the proximal tubule and collecting cells [6]. The precise mechanism of GM-induced nephrotoxicity is still not fully clarified, the principle pathophysiology involves the generation of reactive oxygen species (ROS), apoptosis, increased endothelin-1 levels, and increased cellular infiltration [7]. The previous studies revealed that gentamicin-induced nephrotoxicity involved both glomerular and tubular changes in the form of tubular necrosis, apoptosis of glomerular mesangial cells [13], tubular degeneration associated with swelling, cytosis, and tubular irregularities [14]

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