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


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 (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.


CONCLUSIONS
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.
Lekawanvijit
Suree
S
Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University/Alfred Hospital, Melbourne, VIC 3004, Australia.
Adrahtas
Anastasia
A
Kelly
Darren J
DJ
Kompa
Andrew R
AR
Wang
Bing H
BH
Krum
Henry
H
D000818:Animals; D015153:Blotting, Western; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects*; D007200:Indican / Q000008:administration & dosage / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014118:Toxins, Biological / Q000008:administration & dosage / Q000494:pharmacology*
D016207:Cytokines; D012333:RNA, Messenger; D014118:Toxins, Biological; D007200:Indican