Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducing circulating levels of a non-dialysable uremic toxin, indoxyl sulfate

• Published in: PloS one Vol. 7; no. 7; p. e41281
• Main Authors: Lekawanvijit, Suree, Kompa, Andrew R, Manabe, Minako, Wang, Bing H, Langham, Robyn G, Nishijima, Fuyuhiko, Kelly, Darren J, Krum, Henry
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19-07-2012; Public Library of Science (PLoS)
• Subjects: Actin; Animals; Biology; Blood; Blood pressure; Bone morphogenetic proteins; Carbon - therapeutic use; Cardiomyopathies - blood; Cardiomyopathies - drug therapy; Cardiomyopathies - etiology; Cardiomyopathy; Cardiovascular disease; Charcoal; Chronic kidney failure; Connective tissue growth factor; Coronary artery disease; Coronary vessels; Creatinine; Diabetes; Disease prevention; Echocardiography; Education; Epidemiology; Eutrophication; Fibrosis; Fibrosis - blood; Fibrosis - drug therapy; Fibrosis - etiology; Fuel consumption; Gene expression; Genes; Heart; Heart attacks; Heart diseases; Hemodialysis; Hypertension; Indican - blood; Kidney diseases; Kidney transplantation; Kidneys; Kinases; Major histocompatibility complex; Male; Medicine; Mortality; Muscle proteins; Muscles; NF-κB protein; Oxides - therapeutic use; Preventive medicine; Proteins; Random Allocation; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - complications; Rodents; Scientific imaging; Skeletal muscle; Sulfates; Toxins; Transforming growth factors; Urine; Ventricle; Australia; Melbourne Victoria Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0041281

Cardiovascular death commonly occurs in patients with chronic kidney disease. Indoxyl sulfate (IS), a uremic toxin, has been demonstrated in vitro as a contributory factor in cardiac fibrosis, a typical pathological finding in uremic cardiomyopathy. This study aimed to determine if cardiac fibrosis is reversible by lowering serum IS levels using an oral charcoal adsorbent, AST-120. Subtotal-nephrectomized (5/6-STNx) Sprague-Dawley rats were randomized to receive either AST-120 (AST-120, n=13) or no treatment (vehicle, n=17) for 12 weeks. Sham operated rats (n=12) were used as controls. Early left ventricular (LV) diastolic dysfunction was demonstrated by an increase in peak velocity of atrial filling [A and A' waves] and a decrease of E/A and E'/A' ratios obtained by echocardiography. This was accompanied by a 4.5-fold increase in serum IS (p<0.001) as well as elevated tail-cuff blood pressure (p<0.001) and heart weight (p<0.001). Increased LV fibrosis (p<0.001), gene expression of pro-fibrotic (TGF-β, CTGF) and hypertrophic (ANP, β-MHC and α-skeletal muscle actin) markers, as well as TGF-β and phosphorylated NF-κB protein expression were observed in STNx + vehicle rats. Treatment with AST-120 reduced serum creatinine (by 54%, p<0.05) and urine total protein (by 27%, p<0.05) vs vehicle whilst having no effect on blood pressure (AST-120=227 ± 11 vs vehicle  =224 ± 8 mmHg, ns) and heart weight. The increase in serum IS was prevented with AST-120 (by 100%, p<0.001) which was accompanied by reduced LV fibrosis (68%, p<0.01) and TGF-β and phosphorylated NF-κB protein expression (back to sham levels, p<0.05) despite no significant change in LV function. In conclusion, STNx resulted in increased cardiac fibrosis and circulating IS levels. Reduction of IS with AST-120 normalizes cardiac fibrosis, in a blood pressure independent manner.