Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes?
Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes?
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DOI：
10.1093/eurheartj/ehp574
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发表时间：
2010-07-01
影响因子：
39.3
通讯作者：
Krum, Henry
中科院分区：
文献类型：
--
作者：
Lekawanvijit, Suree;Adrahtas, Anastasia;Krum, Henry
硫酸吲哚酚（IS）是一种高浓度的尿毒症毒素，见于慢性肾脏病（CKD）伴慢性心力衰竭（CHF）患者。本研究的目的是确定IS对心肌细胞的直接作用以及IS的促炎作用。硫酸吲哚酚显著增加新生大鼠心肌成纤维细胞胶原合成（与对照组相比增加145.7%，P < 0.05）和心肌细胞肥大（相对于对照增加134.5%，P < 0.001），如分别通过H-3-脯氨酸或H-3-亮氨酸掺入所测定。硫酸吲哚酚刺激THP-1细胞中肿瘤坏死因子-α、白细胞介素-6（IL-6）和IL-1 β mRNA的表达，如通过RT-PCR定量。p38（RWJ-67657）和MEK 1/2（U 0126）抑制剂均抑制IS的所有这些作用。Western blot分析显示IS激活了丝裂原活化蛋白激酶（MAPK）（p38，p42/44）和核因子-κ B（NF-κ B）通路。3-（4，5-Dimethylthiazol-2-yl）-2，5-diphenyltetrazolium bromide检测显示IS发挥其作用而不影响细胞活力。本研究首次证明IS具有促纤维化、促肥大和促炎症作用，表明IS可能在通过激活p38 MAPK、p42/44 MAPK介导的不良心脏重塑中起重要作用。和NF κ B B途径。靶向减少IS和/或其激活的途径可能代表了管理CHF伴CKD的新治疗方法。
Indoxyl sulfate (IS) is a uraemic toxin found at high concentration in patients with chronic kidney disease (CKD) co-morbid with chronic heart failure (CHF). The aim of this study was to determine direct effects of IS on cardiac cells as well as the pro-inflammatory effect of IS.Indoxyl sulfate significantly increased neonatal rat cardiac fibroblast collagen synthesis (by 145.7% vs. control, P < 0.05) and myocyte hypertrophy (by 134.5% vs. control, P < 0.001) as determined by H-3-proline or H-3-leucine incorporation, respectively. Indoxyl sulfate stimulated tumour necrosis factor-alpha, interleukin-6 (IL-6), and IL-1 beta mRNA expression in THP-1 cells as quantified by RT-PCR. Both p38 (RWJ-67657) and MEK1/2 (U0126) inhibitors suppressed all these effects by IS. Furthermore, western blot analysis showed that IS activated mitogen-activated protein kinase (MAPK) (p38, p42/44) and nuclear factor-kappa B (NF kappa B) pathways. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that IS exerted its effects without affecting cell viability.This study has, for the first time, demonstrated that IS has pro-fibrotic, pro-hypertrophic, and pro-inflammatory effects, indicating that IS might play an important role in adverse cardiac remodelling mediated via activation of the p38 MAPK, p42/44 MAPK, and NF kappa B pathways. Targeting reduction of IS and/or the pathways it activates may represent a novel therapeutic approach to the management of CHF with concomitant CKD.