Abstract
Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via its tubulotoxicity. After cellular uptake, IS directly induces apoptotic and necrotic cell death of tubular cells. Additionally, IS increases oxidative stress and decreases antioxidant capacity, which are associated with tubulointerstitial injury. Injured tubular cells are a major source of transforming growth factor-β1 (TGF-β1), which induces myofibroblast transition from residual renal cells in damaged kidney, recruits inflammatory cells and thereby promotes extracellular matrix deposition in renal fibrosis. Moreover, IS upregulates signal transducers and activators of transcription 3 phosphorylation, followed by increases in TGF-β1, monocyte chemotactic protein-1 and α-smooth muscle actin production, which participate in interstitial inflammation, renal fibrosis and, consequently, CKD progression. Clinically, higher serum IS levels are independently associated with renal function decline and predict all-cause mortality in CKD. The poor removal of serum IS in conventional hemodialysis is also significantly associated with all-cause mortality and heart failure incidence in end-stage renal disease patients. Scavenging the IS precursor by AST-120 can markedly reduce tubular IS staining that attenuates renal tubular injury, ameliorates IS-induced oxidative stress and rescues antioxidant glutathione activity in tubular epithelial cells, thereby providing a protective role against tubular injury and ultimately retarding renal function decline.
Highlights
Taipei Medical University-Research Center of Urology and Kidney, Taipei Medical University, Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Divisions of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei 23148, Taiwan
Renal fibrosis is the inevitable consequence of the excessive accumulation of extracellular matrix (ECM) after renal insults, and fibrosis it is characteristic of glomerular sclerosis, interstitial interstitial infiltration of
Administration of Indoxyl sulfate (IS) in chronic kidney disease (CKD) animals increases the profibrotic factor transforming growth factor-β1 (TGF-β1); tissue inhibitor of metalloproteinase-1 (TIMP-1), an inhibitor to matrix metalloproteinases, which are responsible for ECM degradation; and proα1 (I) collagen, a procollagen precursor expressed in the renal cortex
Summary
A substantial number of compounds that are normally excreted by healthy kidneys are accumulated during renal function deterioration, in which case they are called uremic toxins. Wu et al showed that serum IS levels became higher in OAT1 or OAT3 knockout mice, and these two transporters exerted a synergistic effect in the elimination of solutes or toxins [9]. AST-120 is an oral charcoal absorbent that functions by adsorbing indole generated in the gastrointestinal tract and thereby lowers serum and urine IS concentrations in CKD. Gao et al reported dietary protein restriction is beneficial in CKD progression, meaning that a low-protein diet (LPD) can greatly lower the serum IS level in CKD and prevent proteinuria, alleviate renal lesions and retard renal function decline. A randomized trial conducted by Rossi et al showed that synbiotics could effectively lower p-cresyl sulfate, another uremic toxin, but not IS [18]. New dialysis techniques have reported the potential benefit in reducing IS levels in ESRD patients by including the use of (1) albumin-binding competitor [19], (2) IS transcellular transporter antagonist [20,21] and (3) hydrophobic and cationic adsorbents with high-flux dialyzers [22]
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