Abstract
The accumulation of the uremic toxin indoxyl sulfate (IS) induces target organ damage in chronic kidney disease (CKD) patients, and causes complications including cardiovascular diseases, renal osteodystrophy, muscle wasting, and anemia. IS stimulates reactive oxygen species (ROS) production in CKD, which impairs glomerular filtration by a direct cytotoxic effect on the mesangial cells. IS further reduces antioxidant capacity in renal proximal tubular cells and contributes to tubulointerstitial injury. IS-induced ROS formation triggers the switching of vascular smooth muscular cells to the osteoblastic phenotype, which induces cardiovascular risk. Low-turnover bone disease seen in early CKD relies on the inhibitory effects of IS on osteoblast viability and differentiation, and osteoblastic signaling via the parathyroid hormone. Excessive ROS and inflammatory cytokine releases caused by IS directly inhibit myocyte growth in muscle wasting via myokines’ effects. Moreover, IS triggers eryptosis via ROS-mediated oxidative stress, and elevates hepcidin levels in order to prevent iron flux in circulation in renal anemia. Thus, IS-induced oxidative stress underlies the mechanisms in CKD-related complications. This review summarizes the underlying mechanisms of how IS mediates oxidative stress in the pathogenesis of CKD’s complications. Furthermore, we also discuss the potential role of oral AST-120 in attenuating IS-mediated oxidative stress after gastrointestinal adsorption of the IS precursor indole.
Highlights
Most of these protein-bound uremic toxins are generated by intestinal bacteria fermentation, and include phenolic compounds originated from tyrosine and phenylalanine, as well as indolic compounds originated from tryptophan, such as indoxyl sulfate (IS) [11]
NOX4 is involved in IS-promoted osteoblastic phenotype transition of vascular smooth muscular cells (VSMCs) by increasing osteoblast-specific proteins, alkaline phosphatase, osteopontin, and core-binding factor-1 production [77]. These findings suggest that the accumulation of IS in serum during renal excretory deterioration increases the NOX4mediated oxidative stress burden, and has a deleterious effect on endothelium-dependent vasodilatation and transdifferentiation of VSMCs to the osteoblastic phenotype, which is involved in the development of vascular calcification in chronic kidney disease (CKD) patients
AST-120 has the benefit of improving low-turnover bone disease, which is associated with IS accumulation in CKD
Summary
Antioxidants 2021, 10, 936 oxidative-stress-related redox imbalance is linked to the pathological complications caused by the accumulation of uremic toxins, such as CV disease, renal function decline, uremic bone disease, muscle wasting, and renal anemia [3,4,5,6,7,8]. Protein-bound uremic toxins are hard to remove via dialysis due to their protein-binding capacity, even though their molecular weight is less than 500 daltons Most of these protein-bound uremic toxins are generated by intestinal bacteria fermentation, and include phenolic compounds originated from tyrosine and phenylalanine, as well as indolic compounds originated from tryptophan, such as indoxyl sulfate (IS) [11]. This article summarizes the mechanisms by which IS exerts pro-oxidant influence in CKD patients, and how AST-120, an oral charcoal adsorbent, facilitates IS accumulation and ameliorates IS-mediated organ damage in CKD
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