Involvement of lysyl oxidase in the pathogenesis of arterial stiffness in chronic kidney disease.

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-04-01 Epub Date: 2023-02-24 DOI:10.1152/ajprenal.00239.2022
Ravindra K Sharma, Shyam H Kamble, Suraj Krishnan, Joshua Gomes, Brandon To, Shiyu Li, I-Chia Liu, Michelle L Gumz, Rajesh Mohandas
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Abstract

Patients with chronic kidney disease (CKD) are at increased risk for adverse cardiovascular events. CKD is associated with increases in arterial stiffness, whereas improvements in arterial stiffness correlate with better survival. However, arterial stiffness is increased early in CKD, suggesting that there might be additional factors, unique to kidney disease, that increase arterial stiffness. Lysyl oxidase (LOX) is a key mediator of collagen cross linking and matrix remodeling. LOX is predominantly expressed in the cardiovascular system, and its upregulation has been associated with increased tissue stiffening and extracellular matrix remodeling. Thus, this study was designed to evaluate the role of increased LOX activity in inducing aortic stiffness in CKD and whether β-aminopropionitrile (BAPN), a LOX inhibitor, could prevent aortic stiffness by reducing collagen cross linking. Eight-week-old male C57BL/6 mice were subjected to 5/6 nephrectomy (Nx) or sham surgery. Two weeks after surgery, mice were randomized to BAPN (300 mg/kg/day in water) or vehicle treatment for 4 wk. Aortic stiffness was assessed by pulse wave velocity (PWV) using Doppler ultrasound. Aortic levels of LOX were assessed by ELISA, and cross-linked total collagen levels were analyzed by mass spectrometry and Sircol assay. Nx mice showed increased PWV and aortic wall remodeling compared with control mice. Collagen cross linking was increased in parallel with the increases in total collagen in the aorta of Nx mice. In contrast, Nx mice that received BAPN treatment showed decreased cross-linked collagens and PWV compared with that received vehicle treatment. Our results indicated that LOX might be an early and key mediator of aortic stiffness in CKD.NEW & NOTEWORTHY Arterial stiffness in CKD is associated with adverse cardiovascular outcomes. However, the mechanisms underlying increased aortic stiffness in CKD are unclear. Herein, we demonstrated that 1) increased aortic stiffness in CKD is independent of hypertension and calcification and 2) LOX-mediated changes in extracellular matrix are at least in part responsible for increased aortic stiffness in CKD. Prevention of excess LOX may have therapeutic potential in alleviating increased aortic stiffness and improving cardiovascular disease in CKD.

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赖氨酰氧化酶在慢性肾脏疾病动脉硬化发病机制中的作用。
慢性肾脏病(CKD)患者发生心血管不良事件的风险增加。CKD与动脉硬化增加有关,而动脉硬化的改善与更好的生存率有关。然而,CKD早期动脉硬化增加,这表明可能有肾脏疾病特有的其他因素会增加动脉硬化。赖氨酰氧化酶(LOX)是胶原交联和基质重塑的关键介质。LOX主要在心血管系统中表达,其上调与组织硬化和细胞外基质重塑增加有关。因此,本研究旨在评估LOX活性增加在CKD中诱导主动脉硬化中的作用,以及LOX抑制剂β-氨基丙腈(BAPN)是否可以通过减少胶原交联来预防主动脉硬化。对8周龄雄性C57BL/6小鼠进行5/6肾切除术(Nx)或假手术。手术后两周,将小鼠随机分为BAPN(300mg/kg/天在水中)或载体治疗4周。使用多普勒超声通过脉搏波速度(PWV)评估主动脉硬度。通过ELISA评估主动脉LOX水平,并通过质谱和Sircol测定分析交联总胶原水平。与对照小鼠相比,Nx小鼠表现出PWV和主动脉壁重塑增加。Nx小鼠主动脉中胶原交联的增加与总胶原的增加平行。相反,与接受载体治疗的Nx小鼠相比,接受BAPN治疗的Nx小鼠显示出交联胶原和PWV降低。我们的研究结果表明,LOX可能是CKD主动脉硬化的早期和关键介质。新的和值得注意的是,CKD的动脉硬化与不良心血管后果有关。然而,CKD患者主动脉硬化增加的机制尚不清楚。在此,我们证明1)CKD中主动脉僵硬度的增加与高血压和钙化无关,2)LOX介导的细胞外基质变化至少是CKD主动脉僵硬度增加的部分原因。预防过量LOX可能在缓解CKD患者主动脉硬化增加和改善心血管疾病方面具有治疗潜力。
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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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