Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes?

• Published in: European heart journal 2010-07, Vol.31 (14), p.1771-1779
• Main Authors: Lekawanvijit, Suree, Adrahtas, Anastasia, Kelly, Darren J., Kompa, Andrew R., Wang, Bing H., Krum, Henry
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Cardiology. Vascular system; Cardiomyopathy, Hypertrophic - etiology; Cardiomyopathy, Hypertrophic - pathology; Cell signalling; Cell Survival; Cells, Cultured; Cytokines; Cytokines - metabolism; Dose-Response Relationship, Drug; Fibroblasts - drug effects; Fibrosis; Hypertrophy; Indican - administration & dosage; Indican - pharmacology; Kidney Failure, Chronic - etiology; Kidney Failure, Chronic - pathology; Medical sciences; Myocytes, Cardiac - drug effects; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Rats; Rats, Sprague-Dawley; Renal failure; RNA, Messenger - metabolism; Toxins, Biological - administration & dosage; Toxins, Biological - pharmacology; Uraemic toxins
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehp574

Aims 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. Methods and results 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 3H-proline or 3H-leucine incorporation, respectively. Indoxyl sulfate stimulated tumour necrosis factor-alpha, interleukin-6 (IL-6), and IL-1β 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 (NFκB) pathways. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that IS exerted its effects without affecting cell viability. Conclusion 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 NFκB 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.