Elevated serum creatinine and urea nitrogen levels can lead to renal dysfunction [20, 21]. In particular, increased serum levels of creatinine inhibits glomerular filtration , while high nitrogen levels in blood urea can indicate renal failure to cleanse urea . This experiment found that administering gentamicin led to a significant increase in creatinine, urea, and uric acid in rats. These conform with findings by [24, 25], who also reported increased serum creatinine elevation and blood urea and uric acid, leading to the suggestion that gentamicin is nephrotoxic - although its exact mechanism is unclear. Some studies have implicated ROS formation caused by aminoglycoside antibiotics. Lipid peroxidation generates MDA in the tissues, which inhibits the amount of polyunsaturated fatty acids, which act as a substratum free radicals. This interaction, between phospholipids and aminoglycosides, is the first step in developing gentamycin toxicity . Moreover, Gentamicin forms an Iron-GEN complex, with iron liberated from the renal cortical mitochondria. This also triggers free radical formation and enhances ROS generation .
The increased MDA levels observed in this experiment aligns with the previous research [9, 28], indicating either elevated serum creatinine and urea levels, or elevated MDA in the kidney tissue. This suggests a link between lipid peroxidation and nephrotoxicity, oxidative stress, and kidney dysfunction.
Glutathione plays a critical role in cell maintenance. However, xenobiotics or peroxide-dependent changes in GSH tissue and antioxidant enzyme activity are a contentious topic at the moment . This experiment observed that GSH levels in the kidney are inhibited by gentamicin, correlating with the findings of [29–30]. These works found a link between gentamicin-induced nephrotoxicity, low GSH, and GSH-Px activity in the renal cortex, which might in turn lead to oxidative damage due to decreased antioxidant defenses. Inactivation of GSH-Px, CAT, and SOD would therefore fail to defend against the increased ROS levels produced by gentamicin. Gentamicin accumulates in the renal proximal convoluted tubules, degenerating the brush border membranes, generating free radicals, reducing antioxidant defenses, and causing glomerular congestion, acute tubular necrosis, and ultimately kidney failure [7, 31, 32]. Likewise, gentamicin administration causes renal oxidative damage due to antioxidant defense enzyme deficiencies [33, 34].
Tumor necrosis factor (TNF-α) is implicated in the pathogenesis of acute nephrotoxin-induced renal failure as well as other forms of kidney damage [35, 36]. The administration of gentamicin in our study caused TNF-α to increase significantly. These results are consistent with , who found that gentamicin-induced tubular injury caused inflammation at the site of the necrosis.
The pro-apoptotic gene, Bax, plays a key role, causing the release of cytochrome c, activating procaspase-9. This initiates various caspase streams including caspase-3 , which cleaves specific target proteins, causing the number of apoptotic cells to increase. Conversely, Bcl-2, an antiapoptotic protein, binds to the external membrane of mitochondria, blocking cytochrome c activation .
In this experiment, gentamicin upregulated TNF-α, Bax, and Caspase-3 mRNA expression, and downregulated Bcl-2 mRNA expression. This concurs with [38, 39], whose findings confirmed the same effects of gentamicin administration. From this, it can be conclude that gentamicin therapy can lead to inflammation and apoptosis in renal tissues, followed by necrosis.
The clinical effects of cisplatin are linked to dosage, but high doses can be both nephrotoxic and neurotoxic . Concerning the renal system, cisplatin damages the proximal tubules .
This experiment found that cisplatin administered rats exhibited increased creatinine, urea, and uric acid and this effect was more pronounced than in rats treated with gentamicin, agreeing with the work by [42, 43]. Histopathological observations confirmed damage to the glomerular wall, epithelial degeneration, intertubular hemorrhage, and slight glomerular hypertrophy.
Cisplatin-generated ROS targets organelles, including two microsomes and the mitochondria [44, 45], causing apoptosis and necrosis [46, 47]. Some molecules are also targeted, such as lipids and proteins, causing an increase in MDA and a decrease in the antioxidants GSH and GPx [48, 49]. This work observed that rats administered with cisplatin exhibited increased tissue MDA and reduced kidney GSH, while the production of GSH-Px remained unchanged. These results agree with [50, 51], who recorded imbalanced antioxidant status caused by the buildup of excessive cisplatin-produced ROS. This led to depleted GSH and lipid peroxidation.
Apoptosis is central to many renal disorders, especially those that involve inflammatory processes or induced by nephrotoxic drugs [15, 16]. The present experiment found that cisplatin administration upregulated TNF-α, Bax, and caspase-3 mRNA expression, and downregulated Bcl-2 mRNA expression. These effects were more pronounced than in the gentamycin-administered group and agree with findings by [52–53].