Abstract 1500: Does Indoxyl Sulfate, A Uremic Toxin, Have Direct Effects on Cardiac Fibroblasts & Myocytes?
Introduction: Indoxyl sulfate (IS) is a uremic toxin found at high concentration in patients with chronic kidney disease (CKD), a common accompaniment of chronic heart failure (CHF). While IS has pro-fibrotic effects in renal glomeruli and interstitium, its direct effects on cardiac fibroblast and myocyte function have not as yet been investigated.
Methods: Rat neonatal cardiac fibroblasts (NCF) and myocytes (NCM) were isolated with enzymic digestion and maintained in culture. The effects of IS on NCF collagen synthesis and NCM hypertrophy were determined by 3H-Proline and 3H-Leucine incorporation, respectively. The effects of IS on NCF cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Western blot analysis was used to determine the activation of signal transduction pathways by IS in NCF.
Results: At concentrations tested (0.3μM-100μM) IS significantly increased collagen synthesis in NCF (up to 183.16 % of control). It did not affect NCF cell viability. Stimulation with IS activated p38, p42/p44 MAPKs and NF-κB; RWJ-67657 (p38 MAPK inhibitor) suppressed IS-stimulated collagen synthesis and p38 phosphorylation (Fig 1A&1B⇓). Furthermore, IS also stimulated NCM hypertrophy (152.49–178.84 % of control) (Fig 1C⇓).
Conclusions: IS stimulates collagen synthesis in NCF and hypertrophy in NCM indicating that it might play an important role in cardiac remodelling. These effects may be mediated via activation of the p38, p42/p44 MAPKs, and NF-κB pathways. Targeting reduction of IS or the pathways it activates may represent a novel therapeutic approach to the management of CHF with concomitant CKD.