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Abstract
BackgroundIndoxyl sulfate, a uremic toxin, is accumulated in the serum of chronic kidney disease (CKD) patients, accelerating the progression of CKD. In CKD rat kidney, the expressions of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its related genes are downregulated. AST-120, an oral sorbent, reduces serum indoxyl sulfate and slows the progression of CKD. The present study aimed to determine whether indoxyl sulfate downregulates Nrf2 expression in human proximal tubular cells and rat kidneys and whether AST-120 upregulates Nrf2 expression in CKD rat kidneys.MethodsEffects of indoxyl sulfate on expression of Nrf2 were determined using HK-2 cells as human proximal tubular cells and the following animals: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS). Further, AST-120 was administered to subtotally nephrectomized CKD rats to determine its effect on the expression of Nrf2.ResultsIndoxyl sulfate downregulated Nrf2 expression in HK-2 cells. The indoxyl sulfate-induced downregulation of Nrf2 expression was alleviated by an inhibitor of nuclear factor-κB (NF-κB) (pyrrolidine dithiocarbamate) and small interfering RNA specific to NF-κB p65. DN+IS, DH, and DH+IS rats showed decreased renal expression of Nrf2 and its downstream target genes, heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), and increased renal expression of 8-hydroxydeoxyguanosine (8-OHdG), a marker of reactive oxygen species (ROS), compared with DN. Thus, indoxyl sulfate, as well as hypertension, downregulated renal expression of Nrf2 in rats. AST-120 upregulated renal expression of Nrf2, HO-1 and NQO1 and suppressed renal expression of 8-OHdG compared with control CKD rats.ConclusionsIndoxyl sulfate downregulates renal expression of Nrf2 through activation of NF-κB, followed by downregulation of HO-1 and NQO1 and increased production of ROS. Further, AST-120 upregulates renal expression of Nrf2 in CKD rats by removing serum indoxyl sulfate, followed by upregulation of HO-1 and NQO1 and decreased production of ROS.
Highlights
Indoxyl sulfate, a uremic toxin, is accumulated in the serum of chronic kidney disease (CKD) patients, accelerating the progression of CKD
Reagents Reagents were obtained from the following suppliers: rabbit polyclonal anti-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) for immunohistochemistry and immunoblotting, Santa Cruz Biotechnology (Santa Cruz, CA, USA); rabbit polyclonal anti-heme oxygenase-1 (HO-1) for immunohistochemistry, Abcam (Cambridge, UK); rabbit polyclonal anti-NAD(P)H:quinone oxidoreductase 1 (NQO1) for immunohistochemistry, Abcam (Cambridge, UK); mouse monoclonal anti-8-hydroxydeoxyguanosine (8-OHdG) (MOG-020P) for immunohistochemistry, Japan Institute for the Control of Aging, NIKKEN SEIL, (Shizuoka, Japan); anti-α-tubulin for immunoblotting, Calbiochem (La Jolla, CA, USA); anti-rabbit IgG horseradish peroxidase (HRP)linked antibody, anti-mouse IgG, HRP-linked antibodies, Cell Signaling Technology (Beverly, MA, USA); indoxyl sulfate, Alfa Aesar (Lancashire, UK); pyrrolidine dithiocarbamate (PDTC), Sigma chemical
PDTC alleviated indoxyl sulfate-induced downregulation of both Nrf2 mRNA and protein expression (Figure 2). We further confirmed these results with nuclear factor-κB (NF-κB) p65 siRNA
Summary
A uremic toxin, is accumulated in the serum of chronic kidney disease (CKD) patients, accelerating the progression of CKD. AST-120, an oral sorbent, reduces serum indoxyl sulfate and slows the progression of CKD. A uremic toxin, accelerates the progression of chronic kidney disease (CKD). Indoxyl sulfate induces renal expression of fibrotic genes such as transforming growth factor-β1 (TGF-β1) [4,5] and αsmooth muscle actin (α-SMA) [9,10], inflammatory genes such as monocyte chemotactic protein-1 (MCP-1) [11], and cellular senescence [9,10], and suppresses renal expression of Klotho [8]. AST-120, an oral sorbent, decreases serum level of indoxyl sulfate by adsorbing indole, a precursor of indoxyl sulfate, in the intestine [13,14,15,16,17], and thereby suppresses progression of CKD
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