Chronic Kidney Disease-Induced Cardiac Fibrosis Is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uremic Toxin, Indoxyl Sulfate

作者：Lekawanvijit Suree^*; Kompa Andrew R; Manabe Minako; Wang Bing H; Langham Robyn G; Nishijima Fuyuhiko; Kelly Darren J; Krum Henry

来源：PLos One, 2012, 7(7): e41281.

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%26apos; waves] and a decrease of E/A and E%26apos;/A%26apos; ratios obtained by echocardiography. This was accompanied by a 4.5-fold increase in serum IS (p%26lt;0.001) as well as elevated tail-cuff blood pressure (p%26lt;0.001) and heart weight (p%26lt;0.001). Increased LV fibrosis (p%26lt;0.001), gene expression of pro-fibrotic (TGF-beta, CTGF) and hypertrophic (ANP, beta-MHC and alpha-skeletal muscle actin) markers, as well as TGF-beta and phosphorylated NF-kappa B protein expression were observed in STNx + vehicle rats. Treatment with AST-120 reduced serum creatinine (by 54%, p%26lt;0.05) and urine total protein (by 27%, p%26lt;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%26lt;0.001) which was accompanied by reduced LV fibrosis (68%, p%26lt;0.01) and TGF-beta and phosphorylated NF-kappa B protein expression (back to sham levels, p%26lt;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.

• 出版日期2012-7-19