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Role of nitrergic and endothelin pathways modulations in cisplatin-induced nephrotoxicity in male rats
M W Helmy1, M M Helmy, D M Abd Allah
1Department of Pharmacology and Toxicology, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Egypt. meeshoo7@hotmail.com.
Abstract:
Although the protective role of either nitric oxide (NO) or endothelin (ET) receptors modulation on the severity of cisplatin-induced nephrotoxicity has been recognized in previous studies including our own, the possible interaction between the two pathways remains obscure. In this study, we tested for the first time the possible interaction between the nitrergic and endothelin pathways in cisplatin-induced nephrotoxicity in male rats. Sprague Dawley male rats were divided into four groups: control (given a single dose of normal saline, i.p.), cisplatin (6 mg/kg, i.p.), cisplatin + sildenafil (2 mg/kg, i.p.), cisplatin + sildenafil + BQ-123 (1 mg/kg, i.p.). Each of the co-administered drugs was given in two doses; one hour before and one day after the cisplatin dose. Acute cisplatin administration resulted in significant increases in blood urea nitrogen (BUN) and serum creatinine levels at 96 hours following cisplatin injection. Increased levels of malondialdehyde (MDA), tumor necrosis factor-α (TNF-α) and caspase-3, decreased nitrite/nitrate level and superoxide dismutase (SOD) activity in kidney homogenates were also observed following cisplatin injection, in addition to a typical 'acute tubular necrosis' pattern. According to the obtained results, the co-adminstration of sildenafil alone with cisplatin offered a reno-protective effect comparable to that obtained following the concurrent administration of both sildenafil and the selective ET-A receptor antagonist BQ-123. Thus, the current study is the first to reveal that the presence of an intact NO/cGMP system may offer a moderate reno-protective effect against cisplatin-induced nephrotoxicity even in the presence of ET-A-mediated vasoconstriction, suggesting the absence of obvious functional interaction between the nitrergic and endothelin pathways in cisplatin-induced nephrotoxicity in male rats.
Insights
This study investigated the interaction between nitric oxide (NO) and endothelin (ET) pathways in cisplatin-induced kidney damage. Results show NO pathway modulation offers protection, suggesting no significant interaction with ET-A receptors in this context.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Cisplatin is a widely used chemotherapy agent with significant nephrotoxic potential.
- Both nitric oxide (NO) and endothelin (ET) pathways are implicated in regulating kidney function and injury.
- The interaction between nitrergic and endothelin pathways in cisplatin nephrotoxicity remains poorly understood.
Purpose of the Study:
- To investigate the potential interaction between the nitrergic and endothelin pathways in cisplatin-induced nephrotoxicity in male rats.
- To evaluate the renoprotective effects of modulating these pathways against cisplatin-induced kidney injury.
Main Methods:
- Male Sprague Dawley rats were divided into four groups: control, cisplatin, cisplatin + sildenafil (NO pathway enhancer), and cisplatin + sildenafil + BQ-123 (selective ET-A receptor antagonist).
- Drugs were administered before and after cisplatin injection.
- Renal function was assessed by measuring blood urea nitrogen (BUN) and serum creatinine levels.
- Kidney homogenates were analyzed for oxidative stress markers (MDA, SOD), inflammatory markers (TNF-α), and apoptosis markers (caspase-3), along with nitrite/nitrate levels.
Main Results:
- Cisplatin administration significantly increased BUN and serum creatinine, elevated MDA, TNF-α, and caspase-3, and decreased nitrite/nitrate levels and SOD activity.
- Histopathological examination revealed acute tubular necrosis.
- Sildenafil administration alone provided a renoprotective effect comparable to the combined administration of sildenafil and BQ-123.
Conclusions:
- The nitric oxide/cGMP system offers a moderate renoprotective effect against cisplatin-induced nephrotoxicity.
- There is an absence of obvious functional interaction between the nitrergic and endothelin pathways in cisplatin-induced nephrotoxicity in male rats.
- These findings highlight the potential of targeting the NO pathway for mitigating chemotherapy-induced kidney damage.
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