Fig. 4.

Nephrotoxicity of indoxyl sulfate.

Indoxyl sulfate in the blood is taken up by organic anion transporters (OAT1 and OAT3) at the basolateral membrane of renal tubular cells in which it is accumulated. Indoxyl sulfate generates free radicals, reduces superoxide scavenging activity, and consequently causes tubular cell injury by impairing the kidney’s anti-oxidative systems. The damaged tubular cells produce transforming growth factor (TGF)-β1 as well as chemokines such as intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), osteopontin and endothelin-1 (ET-1). These chemokines promote the infiltration of macrophages which produce TGF-β1. The secreted TGF-β1 stimulates production of tissue inhibitor of metalloproteinase (TIMP)-1 and collagen. The injured tubular cells are transformed into myofibroblasts through an epithelial-to-mesenchymal transition induced by TGF-β1. These changes facilitate interstitial fibrosis. Thus, indoxyl sulfate accumulated in chronic kidney disease (CKD) serum accelerates tubular cell injury and subsequent interstitial fibrosis.