Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University/Alfred Hospital, Melbourne, VIC 3004, Australia.
Eur Heart J. 2010 Jul;31(14):1771-9. doi: 10.1093/eurheartj/ehp574. Epub 2010 Jan 4.
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 (3)H-proline or (3)H-leucine incorporation, respectively. Indoxyl sulfate stimulated tumour necrosis factor-alpha, interleukin-6 (IL-6), and IL-1beta 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 (NFkappaB) 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 NFkappaB 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.
硫酸吲哚酚（IS）是一种在患有慢性肾病（CKD）合并慢性心力衰竭（CHF）的患者中浓度较高的尿毒症毒素。本研究的目的是确定 IS 对心脏细胞的直接作用以及 IS 的促炎作用。
硫酸吲哚酚显著增加了新生大鼠心肌成纤维细胞胶原合成（与对照组相比增加了 145.7%，P < 0.05）和心肌细胞肥大（与对照组相比增加了 134.5%，P < 0.001），分别通过（3）H-脯氨酸或（3）H-亮氨酸掺入来测定。IS 通过 RT-PCR 定量刺激 THP-1 细胞中肿瘤坏死因子-α、白细胞介素-6（IL-6）和白细胞介素-1β mRNA 的表达。p38（RWJ-67657）和 MEK1/2（U0126）抑制剂均抑制了 IS 的所有这些作用。此外，Western blot 分析表明 IS 激活了丝裂原活化蛋白激酶（MAPK）（p38、p42/44）和核因子-κB（NFκB）途径。3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐试验表明，IS 在不影响细胞活力的情况下发挥作用。
本研究首次证明 IS 具有促纤维化、促肥大和促炎作用，表明 IS 可能通过激活 p38 MAPK、p42/44 MAPK 和 NFκB 途径在介导不良心脏重塑中发挥重要作用。靶向降低 IS 及其激活的途径可能代表了一种治疗 CKD 合并 CHF 的新方法。
