N-acetylcysteine treatment attenuates hemodialysis access-related limb pathophysiology in mice with chronic kidney disease.

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-09-01 Epub Date: 2023-07-13 DOI:10.1152/ajprenal.00083.2023
Kyoungrae Kim, Tomas A Cort, Eric M Kunz, Jack Moerschel, Victoria R Palzkill, Gengfu Dong, Chatick N Moparthy, Erik M Anderson, Brian Fazzone, Kerri A O'Malley, Scott T Robinson, Scott A Berceli, Terence E Ryan, Salvatore T Scali
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Abstract

The objective of the present study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery and muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P = 0.0120) and soleus (P = 0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at postoperative day 12 (POD 12) (P = 0.0003), driven by significantly higher grip strength in both male (P = 0.0273) and female (P = 0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on the walking speed at postoperative day 12 (P = 0.0447), and post hoc testing revealed an improvement in NAC-treated male mice (P = 0.0091). The area of postsynaptic acetylcholine receptors (P = 0.0263) and motor endplates (P = 0.0240) was also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation trended higher in NAC-treated female mice but was not statistically significant (P = 0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment attenuated some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation.NEW & NOTEWORTHY Hemodialysis via autogenous arteriovenous fistula (AVF) is the preferred first-line modality for renal replacement therapy in patients with end-stage kidney disease. However, patients undergoing AVF surgery frequently experience a spectrum of hand disability symptoms postsurgery including weakness and neuromotor dysfunction. Unfortunately, no treatment is currently available to prevent or mitigate these symptoms. Here, we provide evidence that daily N-acetylcysteine supplementation can attenuate some aspects of limb neuromotor function in a preclinical mouse model of AVF.

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N-乙酰半胱氨酸治疗可减轻慢性肾脏病小鼠血液透析通路相关的肢体病理生理学。
本研究的目的是确定N-乙酰半胱氨酸(NAC)治疗是否可以减少小鼠与通路相关的肢体功能障碍。雄性和雌性C57BL6J小鼠在髂血管束中手术形成动静脉瘘(AVF)之前,喂食腺嘌呤补充的饮食以诱导慢性肾脏疾病(CKD)。AVF的产生显著增加了主动脉和肾下腔静脉的峰值血流速度,但NAC治疗没有显著影响,表明NAC治疗不影响瘘管成熟。NAC治疗不影响AVF肢体的后肢肌肉和爪子灌注恢复以及肌肉毛细血管密度。然而,NAC治疗显著增加了AVF后胫骨前肌(P=0.0120)和比目鱼肌(P=0.0452)的质量。NAC治疗对术后第12天后肢握力(POD 12)有显著的主要影响(P=0.0003),这是由于接受NAC治疗的雄性(P=0.0273)和雌性(P=0.0031)小鼠的握力显著较高。NAC治疗对术后第12天的行走速度也有显著的主要影响(P=0.047),事后测试显示NAC治疗的雄性小鼠的行走速度有所改善(P=0.0091)。NAC治疗也增加了突触后乙酰胆碱受体(P=0.0263)和运动终板(P=0.0240)的面积。有趣的是,NAC治疗的雌性小鼠后肢骨骼肌线粒体氧化磷酸化趋势更高,但没有统计学意义(P=0.0973)。NAC治疗对任何性别的肌肉谷胱甘肽水平和氧化还原状态都没有显著影响。总之,NAC治疗减轻了AVF产生后患有慢性肾脏疾病的小鼠的神经运动病理学的某些方面。NEW&NOTEWORTHY通过自体动静脉瘘(AVF)进行血液透析是终末期肾病患者首选的肾脏替代治疗一线模式。然而,接受AVF手术的患者在术后经常会出现一系列手部残疾症状,包括虚弱和神经运动功能障碍。不幸的是,目前没有任何治疗方法可以预防或减轻这些症状。在这里,我们提供的证据表明,在AVF的临床前小鼠模型中,每天补充N-乙酰半胱氨酸可以减弱肢体神经运动功能的某些方面。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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