Journal of the Egyptian National Cancer Institute · 2025
Carnitine deficiency augments methotrexate-mediated acute renal injury in rats.
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Selim Fatema Alaa El-Din, Khattab Mahmoud M, Osman Abdel-Moneim M, Karkeet Riham M, Omran Mervat M, Sharaky Marwa, Sayed-Ahmed Mohamed M
Аннотация
BACKGROUND: This research aimed to explore if carnitine (CARN) deficiency is a risk factor in methotrexate (MTX)-mediated acute kidney injury (AKI) and to mechanistically reveal the potential attenuating effect of CARN against MTX-mediated nephrotoxicity.
METHODS: Thirty-six adult male Wister albino rats were subgrouped into six groups. Groups 1, 2, and 3 received 0.9% normal saline (0.5 mL/200 g, i.p.), mildronate (MD, 200 mg/kg/day, i.p.), and L-carnitine (CARN, 200 mg/kg/day, i.p.) for 10 uninterrupted days, respectively. Groups 4, 5, and 6 received similar doses of normal saline, MD, and CARN for 5 days prior to as well as following a solo dose of methotrexate (MTX, 20 mg/kg, i.p.), respectively.
RESULTS: Treatment with a single dose of MTX significantly boosted serum nephrotoxicity as well as hepatotoxicity indices; additionally, it increased the percentage of collagen deposition in rat kidney tissues with obvious histopathological changes. Moreover, MTX lowered kidney levels of adenosine triphosphate (ATP) and amplified acetyl-CoA carboxylase-1 (ACC-1) in kidney tissues. In MD-treated rats, MTX progressively boosted nephrotoxicity indices and collagen disposition in kidney tissues as well as progressive additional reduction in ATP as compared with MTX-treated rats and serum carnitine levels compared with MD-treated rats. Carnitine administration totally counteracted the biochemical and histopathological alterations mediated by MTX to the normal measures.
CONCLUSIONS: This research proposes that carnitine deficiency is a potential risk factor in the development of MTX-mediated AKI. MTX disrupts ACC1 signaling with the consequential inhibition of ATP production. Carnitine supplementation attenuates MTX-mediated AKI. Our results are preliminary and mandate further mechanistic study to justify the progression of AKI by MTX in CARN-deficient rats.
METHODS: Thirty-six adult male Wister albino rats were subgrouped into six groups. Groups 1, 2, and 3 received 0.9% normal saline (0.5 mL/200 g, i.p.), mildronate (MD, 200 mg/kg/day, i.p.), and L-carnitine (CARN, 200 mg/kg/day, i.p.) for 10 uninterrupted days, respectively. Groups 4, 5, and 6 received similar doses of normal saline, MD, and CARN for 5 days prior to as well as following a solo dose of methotrexate (MTX, 20 mg/kg, i.p.), respectively.
RESULTS: Treatment with a single dose of MTX significantly boosted serum nephrotoxicity as well as hepatotoxicity indices; additionally, it increased the percentage of collagen deposition in rat kidney tissues with obvious histopathological changes. Moreover, MTX lowered kidney levels of adenosine triphosphate (ATP) and amplified acetyl-CoA carboxylase-1 (ACC-1) in kidney tissues. In MD-treated rats, MTX progressively boosted nephrotoxicity indices and collagen disposition in kidney tissues as well as progressive additional reduction in ATP as compared with MTX-treated rats and serum carnitine levels compared with MD-treated rats. Carnitine administration totally counteracted the biochemical and histopathological alterations mediated by MTX to the normal measures.
CONCLUSIONS: This research proposes that carnitine deficiency is a potential risk factor in the development of MTX-mediated AKI. MTX disrupts ACC1 signaling with the consequential inhibition of ATP production. Carnitine supplementation attenuates MTX-mediated AKI. Our results are preliminary and mandate further mechanistic study to justify the progression of AKI by MTX in CARN-deficient rats.