Uremic toxicity of indoxyl sulfate.
Indoxyl sulfate, a uremic toxin, is accumulated in the serum of chronic kidney disease (CKD) patients. A part of the dietary protein-derived tryptophan is metabolized into indole by tryptophanase in intestinal bacteria. Indole is absorbed into the blood from the intestine, and is metabolized to indoxyl sulfate in the liver. Indoxyl sulfate is normally excreted into urine. In CKD, however, an inadequate renal clearance of indoxyl sulfate leads to its elevated serum levels. The oral adsorbent AST-120 reduces the serum levels of indoxyl sulfate by adsorbing indole in the intestines and stimulating its excretion into feces. I have proposed a protein metabolite theory by which endogenous protein metabolites such as indoxyl sulfate play a significant role in the progression of CKD. A progressive decline in the glomerular filtration rate leads to increased serum levels of endogenous protein metabolites such as indoxyl sulfate, and to the adverse effects of their overload on the remnant nephrons. Indoxyl sulfate stimulates progressive both tubulointerstitial fibrosis and glomerular sclerosis by increasing the expression of transforming growth factor-beta1, a tissue inhibitor of metalloproteinase-1 and proalpha1 (I) collagen, leading to a further loss of nephrons. AST-120 delays the progression of CKD by removing serum indoxyl sulfate. Moreover, indoxyl sulfate induces oxidative stress in tubular cells, mesangial cells, vascular smooth muscle cells, endothelial cells and osteoblasts as well as stimulating aortic calcification in hypertensive rats, it is also involved in the progression of CKD, cardiovascular disease (CVD) and osteodystrophy. Thus, the removal of indoxyl sulfate by AST-120 ameliorates the progression of not only CKD, but also of CVD and osteodystrophy.
Department of Advanced Medicine for Uremia, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. tniwa@med.nagoya-u.ac.jp
Toshimitsu
T
Niwa
D000818:Animals; D002244:Carbon / Q000494:pharmacology / Q000627:therapeutic use; D005609:Free Radicals; D006801:Humans; D007200:Indican / Q000378:metabolism / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects*; D010006:Osteoblasts / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D014511:Uremia / Q000188:drug therapy / Q000378:metabolism*
D005609:Free Radicals; D010087:Oxides; D002244:Carbon; C040896:AST 120; D007200:Indican