Indoxyl sulfate is a nephro-vascular toxin

Abstract

Indoxyl sulfate is markedly accumulated in the serum of patients with chronic kidney disease (CKD). The oral sorbent AST-120 reduces the serum levels of indoxyl sulfate in CKD patients by adsorbing indole, a precursor of indoxyl sulfate, in the intestine, and thereby stimulating its excretion in feces. AST-120 is used for the treatment of patients with CKD to slow down the progression of CKD. Indoxyl sulfate is taken up by the cells through organic anion transporters (OAT1 and/or OAT3), and induces cellular production of free radicals such as superoxide by activating nicotinamide adenine dinucleotide phosphate oxidase, especially Nox4, thereby impairing the cellular antioxidative system. Indoxyl sulfate induces free radicals in renal tubular cells and glomerular mesangial cells, and stimulates the progression of CKD. I proposed the protein metabolite theory, which states that endogenous protein metabolites such as indoxyl sulfate play a significant role in the progression of CKD by increasing expressions of transforming growth factor-beta1, tissue inhibitor of metalloproteinase-1, and proalpha1(I)collagen. Indoxyl sulfate also induces free radicals in vascular smooth muscle cells and vascular endothelial cells. Indoxyl sulfate stimulates proliferation and osteoblastic transdifferentiation of vascular smooth muscle cells, and inhibits viability and nitric oxide production of vascular endothelial cells. Indoxyl sulfate promotes aortic calcification and aortic wall thickening in hypertensive rats with expression of osteoblast-specific proteins. In conclusion, indoxyl sulfate is a nephro-vascular toxin that is involved in the progression of not only CKD, but also of cardiovascular disease in CKD patients. Therefore, AST-120 may ameliorate the progression of cardiovascular disease as well as of CKD by removing indoxyl sulfate.