Effect of adenosine triphosphate, benidipine and their combinations on bevacizumab-induced kidney damage in rats
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Published on: September 1, 2016
Hüseyin Kocaturk1, Fevzi Bedir1, Ömer Turangezli1
1Department of Urology, Erzurum Regional Training and Research Hospital, Health Sciences University, Turkey.
Background:
Bevacizumab-induced vascular endothelial growth factor (VEGF) inhibition may lead to a decrease in adenosine triphosphate (ATP) levels, an increase in intracellular Na+ and Ca2+ concentrations and an increase in reactive oxygen species (ROS) generation, as well as to cell damage.
Objectives:
To investigate the biochemical and histopathological effects of ATP, benidipine and ATP in combination with benidipine on bevacizumab-induced kidney damage in rats.
Material And Methods:
Rats were divided into 5 treatment groups: bevacizumab (BVZ) alone, ATP + bevacizumab (ABVZ), benidipine + bevacizumab (BBVZ), ATP + benidipine + bevacizumab (ABBVZ), and healthy controls (HC). Adenosine triphosphate (25 mg/kg), benidipine (4 mg/kg orally), ATP (25 mg/kg) + benidipine (4 mg/kg), or saline were administered to albino Wistar rats. One hour after treatment, bevacizumab was injected at a dose of 10 mg/kg to induce kidney damage. Two doses of bevacizumab were delivered 15 days apart. Adenosine triphosphate + benidipine were administered once a day for 1 month.
Results:
Malondialdehyde (MDA), total oxidant status (TOS), creatinine, and blood urea nitrogen (BUN) levels of the BVZ, BBVZ, ABVZ, ABBVZ, and HC groups were ranked from highest to lowest. Conversely, total glutathione (tGSH) and total antioxidant status (TAS) kidney tissue values were ranked from lowest to highest, respectively. Hemorrhage, tubular necrosis and grade 3 focal tubular atrophy were observed in the BVZ group. Atrophy and grade 2 necrosis were observed in the BBVZ group and atrophy and grade 1 necrosis were observed in the ABVZ group. Only grade 1 atrophy was observed in the ABBVZ group.
Conclusions:
Adenosine triphosphate reduced bevacizumab-induced renal toxicity significantly more effectively than benidipine. However, the combination of ATP + benidipine further reduced bevacizumab-induced renal toxicity relative to benidipine or ATP alone. These data indicate that ATP + benidipine might be a potential therapeutic strategy for the prevention of bevacizumab-induced renal toxicity.
Insights
Adenosine triphosphate (ATP) and benidipine combination therapy significantly reduces bevacizumab-induced kidney damage in rats. This combined treatment offers a promising strategy for preventing renal toxicity associated with bevacizumab.
Area of Science:
- Nephrology
- Pharmacology
- Biochemistry
Background:
- Bevacizumab (BVZ) inhibits vascular endothelial growth factor (VEGF), potentially causing kidney damage through reduced adenosine triphosphate (ATP) levels, increased intracellular ions (Na+, Ca2+), and reactive oxygen species (ROS).
- Understanding the biochemical and histopathological consequences of bevacizumab-induced nephrotoxicity is crucial for developing effective countermeasures.
Purpose of the Study:
- To evaluate the protective effects of adenosine triphosphate (ATP) and benidipine, individually and in combination, against bevacizumab-induced kidney damage in a rat model.
- To assess the biochemical and histopathological alterations in rat kidneys following bevacizumab administration and subsequent treatments.
Main Methods:
- Rats received bevacizumab (10 mg/kg) to induce kidney damage, with treatments including ATP (25 mg/kg), benidipine (4 mg/kg), the combination of ATP and benidipine, or saline administered prior to bevacizumab.
- Bevacizumab was administered twice, 15 days apart, while ATP and benidipine treatments were given daily for one month.
- Biochemical markers (MDA, TOS, creatinine, BUN, tGSH, TAS) and histopathological changes (hemorrhage, necrosis, atrophy) were analyzed.
Main Results:
- Bevacizumab treatment significantly increased markers of oxidative stress and kidney damage (MDA, TOS, creatinine, BUN) and decreased antioxidant markers (tGSH, TAS).
- Histopathological examination revealed hemorrhage, tubular necrosis, and focal tubular atrophy in bevacizumab-treated rats.
- ATP alone showed better protection than benidipine alone, significantly reducing kidney damage markers and histopathological findings.
- The combination of ATP and benidipine demonstrated the most significant renoprotective effects, with only grade 1 atrophy observed.
Conclusions:
- Adenosine triphosphate (ATP) is more effective than benidipine in mitigating bevacizumab-induced renal toxicity.
- The combination of ATP and benidipine provides superior protection against bevacizumab-induced kidney damage compared to either agent alone.
- The combined administration of ATP and benidipine presents a potential therapeutic strategy for preventing bevacizumab-related nephrotoxicity.
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