肉碱缺乏会加重甲氨蝶呤介导的大鼠急性肾损伤。

Carnitine deficiency augments methotrexate-mediated acute renal injury in rats.

作者信息

Selim Fatema Alaa El-Din, Khattab Mahmoud M, Osman Abdel-Moneim M, Karkeet Riham M, Omran Mervat M, Sharaky Marwa, Sayed-Ahmed Mohamed M

机构信息

Cairo University, Giza, Egypt.

New Giza University, Giza, Egypt.

出版信息

J Egypt Natl Canc Inst. 2025 Sep 26;37(1):66. doi: 10.1186/s43046-025-00321-y.

DOI:10.1186/s43046-025-00321-y

PMID:41003939

Abstract

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.

摘要

背景

本研究旨在探讨肉碱（CARN）缺乏是否是甲氨蝶呤（MTX）介导的急性肾损伤（AKI）的危险因素，并从机制上揭示肉碱对MTX介导的肾毒性的潜在减轻作用。

方法

将36只成年雄性Wister白化大鼠分为6组。第1、2和3组分别连续10天接受0.9%生理盐水（0.5 mL/200 g，腹腔注射）、米多君（MD，200 mg/kg/天，腹腔注射）和L-肉碱（CARN，200 mg/kg/天，腹腔注射）。第4、5和6组在单次注射甲氨蝶呤（MTX，20 mg/kg，腹腔注射）之前和之后分别接受相似剂量的生理盐水、MD和CARN，持续5天。

结果

单次注射MTX显著提高了血清肾毒性和肝毒性指标；此外，它增加了大鼠肾组织中胶原沉积的百分比，伴有明显的组织病理学变化。此外，MTX降低了肾组织中三磷酸腺苷（ATP）的水平，并增加了肾组织中乙酰辅酶A羧化酶-１（ACC-1）的含量。与MTX处理的大鼠相比，在MD处理的大鼠中，MTX逐渐提高了肾毒性指标和肾组织中的胶原沉积，以及ATP的进一步降低；与MD处理的大鼠相比，血清肉碱水平也有所降低。给予肉碱完全抵消了MTX介导的生化和组织病理学改变，使其恢复到正常水平。