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Toshimitsu Niwa - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE Open Access Indoxyl sulfate, a uremic toxin, downregulates
2016Co-Authors: Graduatedilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background: Indoxyl 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. Methods: Effects 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. Results: Indoxyl 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 an
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Indoxyl Sulfate-Induced Activation of (Pro)Renin Receptor Is Involved in Expression of TGF-β1 and α-Smooth Muscle Actin in Proximal Tubular Cells
Endocrinology, 2014Co-Authors: Shinichi Saito, Hidehisa Shimizu, Fuyuhiko Nishijima, Maimaiti Yisireyili, Atsushi Enomoto, Toshimitsu NiwaAbstract:Activation of (pro)renin receptor (PRR) is involved in the progression of chronic kidney disease. However, the role of Indoxyl sulfate, a uremic toxin, in the activation of PRR is not clear. The present study aimed to clarify the role of Indoxyl sulfate in activation of PRR, in relation to renal expression of fibrotic genes. Renal expression of PRR and renin/prorenin was up-regulated in chronic kidney disease rats compared with normal rats, whereas AST-120 suppressed these expression by reducing serum levels of Indoxyl sulfate. Furthermore, administration of Indoxyl sulfate to normotensive and hypertensive rats increased renal expression of PRR and renin/prorenin. Indoxyl sulfate induced expression of PRR and prorenin in cultured human proximal tubular cells (HK-2 cells). Indoxyl sulfate-induced PRR expression was inhibited by small interfering RNAs of signal transducer and activator of transcription 3 (Stat3) and nuclear factor-κB p65 in proximal tubular cells. N-acetylcysteine, an antioxidant, and diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase, suppressed Indoxyl sulfate-induced PRR expression in proximal tubular cells. N-acetylcysteine prevented Indoxyl sulfate-induced phosphorylation of Stat3 in proximal tubular cells. PRR small interfering RNA inhibited Indoxyl sulfate-induced expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells. Taken together, Indoxyl sulfate-induced up-regulation of prorenin expression and activation of PRR through production of reactive oxygen species and activation of Stat3 and nuclear factor-κB play an important role in the expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells. Thus, Indoxyl sulfate-induced activation of prorenin/PRR might be involved in renal fibrosis.
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Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB.
BMC nephrology, 2013Co-Authors: Dilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background Indoxyl 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.
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Indoxyl Sulfate Enhances p53-TGF-β1-Smad3 Pathway in Proximal Tubular Cells
American journal of nephrology, 2013Co-Authors: Hidehisa Shimizu, Fuyuhiko Nishijima, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background/Aim: Indoxyl sulfate-induced activation of nuclear factor (NF)-ĸB promotes transforming growth factor (TGF)-β1 in human proximal tubular cells (HK-2 cells). The present study aimed to elucidate the cross talk among Indoxyl sulfate, p53 and TGF-β1-Smad3 signaling in proximal tubular cells. Methods: The effects of Indoxyl sulfate on the expression of TGF-β1, Smad3, and α-smooth muscle actin (α-SMA) were determined using HK-2 cells. As for in vivo experiments the following animals were used: Dahl salt-resistant normotensive rats (DN) and Indoxyl sulfate-administered Dahl salt-resistant normotensive rats (DN+IS). Results: Both Indoxyl sulfate and nutlin-3, a specific p53 inducer, stimulated TGF-β1 expression, which was suppressed by pifithrin-α, p-nitro, a p53 inhibitor. Further, Indoxyl sulfate stimulated TGF-β1-induced expression of α-SMA by enhancing Smad3 expression and TGF-β1-induced Smad3 phosphorylation. Indoxyl sulfate induced phosphorylation of extracellular signal-regulated kinase (ERK). U0126, an inhibitor of ERK pathway, prevented Indoxyl sulfate-induced upregulation of Smad3 expression. Immunohistochemistry demonstrated that TGF-β1 and Smad3 were localized in renal tubular cells, and that Indoxyl sulfate increased the TGF-β1 and Smad3-positive area in the kidney. Conclusion: Indoxyl sulfate stimulates p53-induced TGF-β1 expression and TGF-β1-induced α-SMA expression in proximal tubular cells. Indoxyl sulfate-induced Smad3 accelerates TGF-β1-induced α-SMA expression through ERK activation. Thus, Indoxyl sulfate enhances p53-TGF-β1-Smad3 pathway in proximal tubular cells.
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Indoxyl Sulfate Counteracts Endothelial Effects of Erythropoietin Through Suppression of Akt Phosphorylation
Circulation journal : official journal of the Japanese Circulation Society, 2013Co-Authors: Yelixiati Adelibieke, Shinichi Saito, Hidehisa Shimizu, Roumyana Mironova, Toshimitsu NiwaAbstract:Background: Erythropoietin (EPO) is used to treat anemia in patients with chronic kidney disease (CKD). A wide variation in individual response to EPO, however, is often observed, causing EPO resistance. EPO exhibits not only hematopoietic but also extra-hematopoietic functions such as endothelial effects. Indoxyl sulfate, a uremic toxin, is involved in endothelial dysfunction, and consequently, the pathogenesis of CKD-associated cardiovascular disease. The aim of the present study was to determine the effect of Indoxyl sulfate on the extra-hematopoietic functions of EPO in human umbilical vein endothelial cells (HUVECs). Methods and Results: HUVECs were incubated with or without Indoxyl sulfate or an Akt inhibitor, and then stimulated with or without EPO. Indoxyl sulfate suppressed EPO-induced survival/proliferation, anti-apoptosis function, phosphorylation of endothelial nitric oxide synthase, and the expression of thrombospondin-1, an erythroid-stimulating factor, in HUVECs. Although EPO induced phosphorylation of both Akt and extracellular signal-regulated kinases (ERK) in HUVECs, Indoxyl sulfate suppressed phosphorylation of Akt but not ERK. An Akt kinase inhibitor or Akt small interfering RNA suppressed all the EPO-induced cellular effects in HUVECs. As a site of action of Indoxyl sulfate on EPO signaling, Indoxyl sulfate attenuated EPO-induced tyrosine phosphorylation of EPO receptor (EPOR) in HUVECs. Conclusions: Indoxyl sulfate negatively regulates the EPOR-Akt pathway in endothelial cells, and might contribute to EPO resistance and endothelial dysfunction in patients with CKD. (Circ J 2013; 77: 1326–1336)
Hidehisa Shimizu - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE Open Access Indoxyl sulfate, a uremic toxin, downregulates
2016Co-Authors: Graduatedilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background: Indoxyl 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. Methods: Effects 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. Results: Indoxyl 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 an
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Indoxyl Sulfate-Induced Activation of (Pro)Renin Receptor Is Involved in Expression of TGF-β1 and α-Smooth Muscle Actin in Proximal Tubular Cells
Endocrinology, 2014Co-Authors: Shinichi Saito, Hidehisa Shimizu, Fuyuhiko Nishijima, Maimaiti Yisireyili, Atsushi Enomoto, Toshimitsu NiwaAbstract:Activation of (pro)renin receptor (PRR) is involved in the progression of chronic kidney disease. However, the role of Indoxyl sulfate, a uremic toxin, in the activation of PRR is not clear. The present study aimed to clarify the role of Indoxyl sulfate in activation of PRR, in relation to renal expression of fibrotic genes. Renal expression of PRR and renin/prorenin was up-regulated in chronic kidney disease rats compared with normal rats, whereas AST-120 suppressed these expression by reducing serum levels of Indoxyl sulfate. Furthermore, administration of Indoxyl sulfate to normotensive and hypertensive rats increased renal expression of PRR and renin/prorenin. Indoxyl sulfate induced expression of PRR and prorenin in cultured human proximal tubular cells (HK-2 cells). Indoxyl sulfate-induced PRR expression was inhibited by small interfering RNAs of signal transducer and activator of transcription 3 (Stat3) and nuclear factor-κB p65 in proximal tubular cells. N-acetylcysteine, an antioxidant, and diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase, suppressed Indoxyl sulfate-induced PRR expression in proximal tubular cells. N-acetylcysteine prevented Indoxyl sulfate-induced phosphorylation of Stat3 in proximal tubular cells. PRR small interfering RNA inhibited Indoxyl sulfate-induced expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells. Taken together, Indoxyl sulfate-induced up-regulation of prorenin expression and activation of PRR through production of reactive oxygen species and activation of Stat3 and nuclear factor-κB play an important role in the expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells. Thus, Indoxyl sulfate-induced activation of prorenin/PRR might be involved in renal fibrosis.
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Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB.
BMC nephrology, 2013Co-Authors: Dilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background Indoxyl 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.
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Indoxyl Sulfate Enhances p53-TGF-β1-Smad3 Pathway in Proximal Tubular Cells
American journal of nephrology, 2013Co-Authors: Hidehisa Shimizu, Fuyuhiko Nishijima, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background/Aim: Indoxyl sulfate-induced activation of nuclear factor (NF)-ĸB promotes transforming growth factor (TGF)-β1 in human proximal tubular cells (HK-2 cells). The present study aimed to elucidate the cross talk among Indoxyl sulfate, p53 and TGF-β1-Smad3 signaling in proximal tubular cells. Methods: The effects of Indoxyl sulfate on the expression of TGF-β1, Smad3, and α-smooth muscle actin (α-SMA) were determined using HK-2 cells. As for in vivo experiments the following animals were used: Dahl salt-resistant normotensive rats (DN) and Indoxyl sulfate-administered Dahl salt-resistant normotensive rats (DN+IS). Results: Both Indoxyl sulfate and nutlin-3, a specific p53 inducer, stimulated TGF-β1 expression, which was suppressed by pifithrin-α, p-nitro, a p53 inhibitor. Further, Indoxyl sulfate stimulated TGF-β1-induced expression of α-SMA by enhancing Smad3 expression and TGF-β1-induced Smad3 phosphorylation. Indoxyl sulfate induced phosphorylation of extracellular signal-regulated kinase (ERK). U0126, an inhibitor of ERK pathway, prevented Indoxyl sulfate-induced upregulation of Smad3 expression. Immunohistochemistry demonstrated that TGF-β1 and Smad3 were localized in renal tubular cells, and that Indoxyl sulfate increased the TGF-β1 and Smad3-positive area in the kidney. Conclusion: Indoxyl sulfate stimulates p53-induced TGF-β1 expression and TGF-β1-induced α-SMA expression in proximal tubular cells. Indoxyl sulfate-induced Smad3 accelerates TGF-β1-induced α-SMA expression through ERK activation. Thus, Indoxyl sulfate enhances p53-TGF-β1-Smad3 pathway in proximal tubular cells.
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Indoxyl Sulfate Counteracts Endothelial Effects of Erythropoietin Through Suppression of Akt Phosphorylation
Circulation journal : official journal of the Japanese Circulation Society, 2013Co-Authors: Yelixiati Adelibieke, Shinichi Saito, Hidehisa Shimizu, Roumyana Mironova, Toshimitsu NiwaAbstract:Background: Erythropoietin (EPO) is used to treat anemia in patients with chronic kidney disease (CKD). A wide variation in individual response to EPO, however, is often observed, causing EPO resistance. EPO exhibits not only hematopoietic but also extra-hematopoietic functions such as endothelial effects. Indoxyl sulfate, a uremic toxin, is involved in endothelial dysfunction, and consequently, the pathogenesis of CKD-associated cardiovascular disease. The aim of the present study was to determine the effect of Indoxyl sulfate on the extra-hematopoietic functions of EPO in human umbilical vein endothelial cells (HUVECs). Methods and Results: HUVECs were incubated with or without Indoxyl sulfate or an Akt inhibitor, and then stimulated with or without EPO. Indoxyl sulfate suppressed EPO-induced survival/proliferation, anti-apoptosis function, phosphorylation of endothelial nitric oxide synthase, and the expression of thrombospondin-1, an erythroid-stimulating factor, in HUVECs. Although EPO induced phosphorylation of both Akt and extracellular signal-regulated kinases (ERK) in HUVECs, Indoxyl sulfate suppressed phosphorylation of Akt but not ERK. An Akt kinase inhibitor or Akt small interfering RNA suppressed all the EPO-induced cellular effects in HUVECs. As a site of action of Indoxyl sulfate on EPO signaling, Indoxyl sulfate attenuated EPO-induced tyrosine phosphorylation of EPO receptor (EPOR) in HUVECs. Conclusions: Indoxyl sulfate negatively regulates the EPOR-Akt pathway in endothelial cells, and might contribute to EPO resistance and endothelial dysfunction in patients with CKD. (Circ J 2013; 77: 1326–1336)
Fuyuhiko Nishijima - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE Open Access Indoxyl sulfate, a uremic toxin, downregulates
2016Co-Authors: Graduatedilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background: Indoxyl 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. Methods: Effects 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. Results: Indoxyl 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 an
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Indoxyl Sulfate-Induced Activation of (Pro)Renin Receptor Is Involved in Expression of TGF-β1 and α-Smooth Muscle Actin in Proximal Tubular Cells
Endocrinology, 2014Co-Authors: Shinichi Saito, Hidehisa Shimizu, Fuyuhiko Nishijima, Maimaiti Yisireyili, Atsushi Enomoto, Toshimitsu NiwaAbstract:Activation of (pro)renin receptor (PRR) is involved in the progression of chronic kidney disease. However, the role of Indoxyl sulfate, a uremic toxin, in the activation of PRR is not clear. The present study aimed to clarify the role of Indoxyl sulfate in activation of PRR, in relation to renal expression of fibrotic genes. Renal expression of PRR and renin/prorenin was up-regulated in chronic kidney disease rats compared with normal rats, whereas AST-120 suppressed these expression by reducing serum levels of Indoxyl sulfate. Furthermore, administration of Indoxyl sulfate to normotensive and hypertensive rats increased renal expression of PRR and renin/prorenin. Indoxyl sulfate induced expression of PRR and prorenin in cultured human proximal tubular cells (HK-2 cells). Indoxyl sulfate-induced PRR expression was inhibited by small interfering RNAs of signal transducer and activator of transcription 3 (Stat3) and nuclear factor-κB p65 in proximal tubular cells. N-acetylcysteine, an antioxidant, and diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase, suppressed Indoxyl sulfate-induced PRR expression in proximal tubular cells. N-acetylcysteine prevented Indoxyl sulfate-induced phosphorylation of Stat3 in proximal tubular cells. PRR small interfering RNA inhibited Indoxyl sulfate-induced expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells. Taken together, Indoxyl sulfate-induced up-regulation of prorenin expression and activation of PRR through production of reactive oxygen species and activation of Stat3 and nuclear factor-κB play an important role in the expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells. Thus, Indoxyl sulfate-induced activation of prorenin/PRR might be involved in renal fibrosis.
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Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB.
BMC nephrology, 2013Co-Authors: Dilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background Indoxyl 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.
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Indoxyl Sulfate Enhances p53-TGF-β1-Smad3 Pathway in Proximal Tubular Cells
American journal of nephrology, 2013Co-Authors: Hidehisa Shimizu, Fuyuhiko Nishijima, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background/Aim: Indoxyl sulfate-induced activation of nuclear factor (NF)-ĸB promotes transforming growth factor (TGF)-β1 in human proximal tubular cells (HK-2 cells). The present study aimed to elucidate the cross talk among Indoxyl sulfate, p53 and TGF-β1-Smad3 signaling in proximal tubular cells. Methods: The effects of Indoxyl sulfate on the expression of TGF-β1, Smad3, and α-smooth muscle actin (α-SMA) were determined using HK-2 cells. As for in vivo experiments the following animals were used: Dahl salt-resistant normotensive rats (DN) and Indoxyl sulfate-administered Dahl salt-resistant normotensive rats (DN+IS). Results: Both Indoxyl sulfate and nutlin-3, a specific p53 inducer, stimulated TGF-β1 expression, which was suppressed by pifithrin-α, p-nitro, a p53 inhibitor. Further, Indoxyl sulfate stimulated TGF-β1-induced expression of α-SMA by enhancing Smad3 expression and TGF-β1-induced Smad3 phosphorylation. Indoxyl sulfate induced phosphorylation of extracellular signal-regulated kinase (ERK). U0126, an inhibitor of ERK pathway, prevented Indoxyl sulfate-induced upregulation of Smad3 expression. Immunohistochemistry demonstrated that TGF-β1 and Smad3 were localized in renal tubular cells, and that Indoxyl sulfate increased the TGF-β1 and Smad3-positive area in the kidney. Conclusion: Indoxyl sulfate stimulates p53-induced TGF-β1 expression and TGF-β1-induced α-SMA expression in proximal tubular cells. Indoxyl sulfate-induced Smad3 accelerates TGF-β1-induced α-SMA expression through ERK activation. Thus, Indoxyl sulfate enhances p53-TGF-β1-Smad3 pathway in proximal tubular cells.
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Stat3 contributes to Indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence.
American journal of nephrology, 2012Co-Authors: Hidehisa Shimizu, Fuyuhiko Nishijima, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background/Aim: Increased phosphorylation (activation) of signal transducer and activator of transcription 3 (Stat3) on tyrosine 705 leads to renal fibrosis. Indoxyl sulfate, a uremic toxin, induces renal fibrosis through expression of transforming growth factor-β1 (TGF-β1) in proximal tubular cells. The present study aimed to determine whether Stat3 is involved in Indoxyl sulfate-induced dysfunction of proximal tubular cells. Methods: Localization of phosphorylated Stat3 in the kidneys of normal, subtotally nephrectomized, and AST-120-treated subtotally nephrectomized rats was examined by immunohistochemistry. The effect of Indoxyl sulfate on phosphorylation of Stat3 and the role of Stat3 on Indoxyl sulfate-induced cellular effects were examined using human proximal tubular cells (HK-2 cells). Results: Subtotally nephrectomized rats showed increased immunostaining of phosphorylated Stat3 in the renal tubules compared with normal rats. Administration of AST-120, which reduces serum level of Indoxyl sulfate, to subtotally nephrectomized rats reduced the immunostaining of phosphorylated Stat3 in the renal tubules. Indoxyl sulfate induced phosphorylation of Stat3 in HK-2 cells. Stat3 small interfering RNA suppressed Indoxyl sulfate-induced expression of an inflammation marker gene (monocyte chemotactic protein-1), fibrosis marker genes (TGF-β1, α-smooth muscle actin) and a subunit of nuclear factor-ĸB (p65), and attenuated a cellular senescence marker, senescence-associated β-galactosidase activity. Conclusions: Stat3 is involved in Indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence in proximal tubular cells.
Takashi Miyazaki - One of the best experts on this subject based on the ideXlab platform.
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an oral sorbent reduces overload of Indoxyl sulphate and gene expression of tgf β1 in uraemic rat kidneys
Nephrology Dialysis Transplantation, 2000Co-Authors: Takashi Miyazaki, Michihito Ise, Isao Aoyama, Hisao Seo, Toshimitsu NiwaAbstract:Background. An oral adsorbent (AST-120) delays the progression of chronic renal failure (CRF ). The aims of the present study are to determine the effects of AST-120 on the localization of Indoxyl sulphate in Introduction uraemic rat kidneys, and to examine whether AST-120 reduces the renal cortical gene expression of trans- Circulating uraemic toxins are thought to be one of forming growth factor ( TGF )-b1, tissue inhibitor of the causes accelerating the progression of chronic renal metalloproteinase ( TIMP)-1 and pro-a1(I )collagen, failure (CRF ), since Motojima et al. [1] reported that and ameliorates glomerular and tubulointerstitial peritoneal dialysis and the administration of an oral injuries in uraemic rats. adsorbent (AST-120; Kremezin, Kureha-Chemical Methods. Two weeks after 5/6-nephrectomy, 10 rats Co., Tokyo, Japan) slowed the progression of glomerwere divided into pairs such that both rats in each pair ular sclerosis in 7/8-nephrectomized rats. Thus far, exhibited almost the same levels of serum creatinine, there have been several reports that the administration blood urea nitrogen and creatinine clearance. One rat of AST-120 retards the progression of CRF in both from each pair was assigned to a control uraemic uraemic rats [2,3] and undialysed uraemic patients group, the other to a uraemic group which received [4–6 ]. AST-120 consists of fine spherical particles AST-120 everyday for 11 weeks. The localization of approximately 0.2–0.4 mm in diameter, composed of Indoxyl sulphate was studied by immunohistochemistry porous microcrystalline carbon with an oxygen comusing a monoclonal anti-Indoxyl sulphate antibody we plex including a surface oxide. It adsorbs hydrophobic had developed. The renal cortical gene expression was uraemic substances in the gastrointestinal tract, and is studied by using northern blotting. excreted into faeces. AST-120 is soluble neither in Results. Rats treated with AST-120 showed decreased water nor in organic solvents. It is not decomposed by levels of serum creatinine, blood urea nitrogen and digestive enzymes or intestinal bacteria, and does not urinary protein as well as increased levels of creatinine adsorb electrolytes such as sodium, potassium, calcium clearance as compared with control uraemic rats. or phosphate. At present, AST-120 is widely used as AST-120 markedly decreased Indoxyl sulphate levels an approved drug in Japan for the treatment of in both serum and urine. Immunohistochemistry approximately 20 000 undialysed uraemic patients to demonstrated that Indoxyl sulphate was localized in the delay the progression of CRF. However, AST-120 is renal proximal tubular epithelial cells, especially of not yet available outside Japan. dilated tubules, and that AST-120 markedly reduced We have demonstrated that Indoxyl sulphate is one the tubular staining of Indoxyl sulphate. AST-120 of the circulating uraemic toxins accelerating the proattenuated interstitial fibrosis, tubular injury as well as gression of CRF [7–10]. Indoxyl sulphate is derived glomerular sclerosis, and reduced the renal gene expres- from dietary protein. A part of protein-derived tryptosion of TGF-b1, TIMP-1 and pro-a1(I )collagen. phan is metabolized into indole by tryptophanase in Conclusions. AST-120 reduces the gene expression of intestinal bacteria such as Escherichia coli. Indole is TGF-b1, TIMP-1 and pro-a1(I )collagen in the kid- absorbed into the blood from the intestine, and is neys, and delays the progression of CRF, at least in metabolized to Indoxyl sulphate in the liver. Indoxyl part, by alleviating the overload of Indoxyl sulphate sulphate is normally excreted into urine. In uraemia, on remnant proximal tubular epithelial cells. however, reduced renal clearance of Indoxyl sulphate leads to elevated serum levels of Indoxyl sulphate. In
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Urinary Indoxyl sulfate is a clinical factor that affects the progression of renal failure.
Mineral and electrolyte metabolism, 1999Co-Authors: Toshimitsu Niwa, Fumio Takayama, Takashi Miyazaki, S Tsukushi, Akira Owada, Isao Aoyama, Tatsuo ShiigaiAbstract:We recently demonstrated that Indoxyl sulfate is a stimulating factor for the progression of chronic renal failure (CRF). In this study we determined whether the urine or serum levels of Indoxyl sulfa
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the protein metabolite hypothesis a model for the progression of renal failure an oral adsorbent lowers Indoxyl sulfate levels in undialyzed uremic patients
Kidney International, 1997Co-Authors: Toshimitsu Niwa, T Nomura, S Sugiyama, Takashi Miyazaki, S Tsukushi, S TsutsuiAbstract:The protein metabolite hypothesis, a model for the progression of renal failure: An oral adsorbent lowers Indoxyl sulfate levels in undialyzed uremic patients. We have recently demonstrated that Indoxyl sulfate promotes the progression of glomerular sclerosis in uremic rats. In the present study, we determined whether an oral adsorbent (AST-120) could reduce the serum and urine levels of Indoxyl sulfate and suppress the progression of chronic renal failure (CRF) in undialyzed uremic patients. Twenty-five undialyzed uremic patients were given AST-120 at a dose of 6 g/day for 6 months, whil e 10 undialyzed uremic patients were not given AST-120. The effects of the oral adsorbent on the slope of the 1/serum creatinine (S c,)-time plot, and the serum and urine levels of Indoxyl sulfate were evaluated. Administration of AST-120 significantly decreased the serum and urine levels of Indoxyl sulfate, and tended to improve the slope of the 1/Sc,-time plot in the CRF patients. Among the patients in whom urinary excretion of Indoxyl sulfate was reduced by AST-120, the oral adsorbent significantly improved the slope of the 1/Sc,·tim e plot. The change in the slope of the 1/Sc,-time plot showed a significant negative correlation with the change in the urine level of Indoxyl su lfate. Thus, patients who showed a greater decrease of urinary Indoxyl sulfate also showed more marked suppression of the progression of CRF. These results support the notion that Indoxyl sulfate, a protein metabolite, is involved in the progression of CRF, and that an oral adsorbent can delay progression at least partly by reducing the serum and urine levels of Indoxyl sulfate.
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Indoxyl sulfate increases the gene expressions of tgf beta 1 timp 1 and pro alpha 1 i collagen in uremic rat kidneys
Kidney International, 1997Co-Authors: Takashi Miyazaki, M Ise, H Seo, T NiwaAbstract:We recently reported that the serum levels of Indoxyl sulfate, a dietary protein metabolite, are increased in both uremic rats and patients, and that the administration of Indoxyl sulfate to uremic rats accelerates the progression of glomerular sclerosis. Thus, we hypothesize that the overload of protein metabolites such as Indoxyl sulfate on nephrons promotes the progression of chronic renal failure (CRF). Recent studies revealed that tubulointerstitial injury is of equal or greater importance than glomerular sclerosis in determining whether progressive renal dysfunction will ensue in various renal diseases. In the present study, to clarify the role of Indoxyl sulfate in the progression of CRF, the expressions of genes related to tubulointerstitial fibrosis such as transforming growth factor (TGF)-beta 1, tissue inhibitor of metalloproteinases (TIMP-1) and pro-alpha 1(I) collagen were examined in the renal cortex of 5/6-nephrectomized uremic rats given Indoxyl sulfate. In the first experiment, the administration of Indoxyl sulfate for five weeks significantly increased the mRNA levels of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in the uremic rats given Indoxyl sulfate compared with the control uremic rats, accompanied by a significant decline in renal function and worsening of glomerular sclerosis. In the second experiment, the administration of Indoxyl sulfate for 2.5 weeks also increased the expression of the mRNA levels with no significant decline in the renal function. In conclusion, these findings indicate that the overload of the protein metabolite Indoxyl sulfate on remnant nephrons is involved in the increased bioactivity of TGF-beta 1 in uremic kidneys, which enhances the renal expression of TIMP-1 and type 1 collagen, leading to the progression of CRF.
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Indoxyl sulfate and progression of renal failure: effects of a low-protein diet and oral sorbent on Indoxyl sulfate production in uremic rats and undialyzed uremic patients.
Mineral and electrolyte metabolism, 1997Co-Authors: Toshimitsu Niwa, Ise M, Takashi Miyazaki, S Tsukushi, Yoshiharu Tsubakihara, Akira Owada, Tatsuo ShiigaiAbstract:We have previously demonstrated that Indoxyl sulfate is a stimulating factor for the progression of glomerular sclerosis in uremic rats. In this study we determined if a low-protein diet or oral sorbent (AST-120) could reduce the serum and urine levels of Indoxyl sulfate in 5/6-nephrectomized uremic rats and undialyzed uremic patients. The uremic rats were treated by fasting or AST-120 for 2 days. The serum and urine levels of Indoxyl sulfate dramatically decreased 1-2 days after fasting or AST-120 treatment. We then measured the serum and urine levels of Indoxyl sulfate and calculated protein intake from urinary amounts of urea nitrogen using Maroni's equation in 80 undialyzed uremic patients with creatinine clearance less than 30 ml/min. The serum and urine levels of Indoxyl sulfate were significantly lower in the patients on a low-protein diet than in those in the normal-protein diet group. Administration of AST-120 significantly decreased serum and urine levels of Indoxyl sulfate in 22 undialyzed uremic patients. In conclusion, a low-protein diet or AST-120 reduced the serum and urine levels of Indoxyl sulfate, a stimulating factor for glomerular sclerosis, in both uremic rats and undialyzed uremic patients.
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RESEARCH ARTICLE Open Access Indoxyl sulfate, a uremic toxin, downregulates
2016Co-Authors: Graduatedilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background: Indoxyl 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. Methods: Effects 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. Results: Indoxyl 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 an
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Indoxyl Sulfate-Induced Activation of (Pro)Renin Receptor Is Involved in Expression of TGF-β1 and α-Smooth Muscle Actin in Proximal Tubular Cells
Endocrinology, 2014Co-Authors: Shinichi Saito, Hidehisa Shimizu, Fuyuhiko Nishijima, Maimaiti Yisireyili, Atsushi Enomoto, Toshimitsu NiwaAbstract:Activation of (pro)renin receptor (PRR) is involved in the progression of chronic kidney disease. However, the role of Indoxyl sulfate, a uremic toxin, in the activation of PRR is not clear. The present study aimed to clarify the role of Indoxyl sulfate in activation of PRR, in relation to renal expression of fibrotic genes. Renal expression of PRR and renin/prorenin was up-regulated in chronic kidney disease rats compared with normal rats, whereas AST-120 suppressed these expression by reducing serum levels of Indoxyl sulfate. Furthermore, administration of Indoxyl sulfate to normotensive and hypertensive rats increased renal expression of PRR and renin/prorenin. Indoxyl sulfate induced expression of PRR and prorenin in cultured human proximal tubular cells (HK-2 cells). Indoxyl sulfate-induced PRR expression was inhibited by small interfering RNAs of signal transducer and activator of transcription 3 (Stat3) and nuclear factor-κB p65 in proximal tubular cells. N-acetylcysteine, an antioxidant, and diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase, suppressed Indoxyl sulfate-induced PRR expression in proximal tubular cells. N-acetylcysteine prevented Indoxyl sulfate-induced phosphorylation of Stat3 in proximal tubular cells. PRR small interfering RNA inhibited Indoxyl sulfate-induced expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells. Taken together, Indoxyl sulfate-induced up-regulation of prorenin expression and activation of PRR through production of reactive oxygen species and activation of Stat3 and nuclear factor-κB play an important role in the expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells. Thus, Indoxyl sulfate-induced activation of prorenin/PRR might be involved in renal fibrosis.
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Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB.
BMC nephrology, 2013Co-Authors: Dilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background Indoxyl 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.
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Indoxyl Sulfate Enhances p53-TGF-β1-Smad3 Pathway in Proximal Tubular Cells
American journal of nephrology, 2013Co-Authors: Hidehisa Shimizu, Fuyuhiko Nishijima, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background/Aim: Indoxyl sulfate-induced activation of nuclear factor (NF)-ĸB promotes transforming growth factor (TGF)-β1 in human proximal tubular cells (HK-2 cells). The present study aimed to elucidate the cross talk among Indoxyl sulfate, p53 and TGF-β1-Smad3 signaling in proximal tubular cells. Methods: The effects of Indoxyl sulfate on the expression of TGF-β1, Smad3, and α-smooth muscle actin (α-SMA) were determined using HK-2 cells. As for in vivo experiments the following animals were used: Dahl salt-resistant normotensive rats (DN) and Indoxyl sulfate-administered Dahl salt-resistant normotensive rats (DN+IS). Results: Both Indoxyl sulfate and nutlin-3, a specific p53 inducer, stimulated TGF-β1 expression, which was suppressed by pifithrin-α, p-nitro, a p53 inhibitor. Further, Indoxyl sulfate stimulated TGF-β1-induced expression of α-SMA by enhancing Smad3 expression and TGF-β1-induced Smad3 phosphorylation. Indoxyl sulfate induced phosphorylation of extracellular signal-regulated kinase (ERK). U0126, an inhibitor of ERK pathway, prevented Indoxyl sulfate-induced upregulation of Smad3 expression. Immunohistochemistry demonstrated that TGF-β1 and Smad3 were localized in renal tubular cells, and that Indoxyl sulfate increased the TGF-β1 and Smad3-positive area in the kidney. Conclusion: Indoxyl sulfate stimulates p53-induced TGF-β1 expression and TGF-β1-induced α-SMA expression in proximal tubular cells. Indoxyl sulfate-induced Smad3 accelerates TGF-β1-induced α-SMA expression through ERK activation. Thus, Indoxyl sulfate enhances p53-TGF-β1-Smad3 pathway in proximal tubular cells.
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Stat3 contributes to Indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence.
American journal of nephrology, 2012Co-Authors: Hidehisa Shimizu, Fuyuhiko Nishijima, Maimaiti Yisireyili, Toshimitsu NiwaAbstract:Background/Aim: Increased phosphorylation (activation) of signal transducer and activator of transcription 3 (Stat3) on tyrosine 705 leads to renal fibrosis. Indoxyl sulfate, a uremic toxin, induces renal fibrosis through expression of transforming growth factor-β1 (TGF-β1) in proximal tubular cells. The present study aimed to determine whether Stat3 is involved in Indoxyl sulfate-induced dysfunction of proximal tubular cells. Methods: Localization of phosphorylated Stat3 in the kidneys of normal, subtotally nephrectomized, and AST-120-treated subtotally nephrectomized rats was examined by immunohistochemistry. The effect of Indoxyl sulfate on phosphorylation of Stat3 and the role of Stat3 on Indoxyl sulfate-induced cellular effects were examined using human proximal tubular cells (HK-2 cells). Results: Subtotally nephrectomized rats showed increased immunostaining of phosphorylated Stat3 in the renal tubules compared with normal rats. Administration of AST-120, which reduces serum level of Indoxyl sulfate, to subtotally nephrectomized rats reduced the immunostaining of phosphorylated Stat3 in the renal tubules. Indoxyl sulfate induced phosphorylation of Stat3 in HK-2 cells. Stat3 small interfering RNA suppressed Indoxyl sulfate-induced expression of an inflammation marker gene (monocyte chemotactic protein-1), fibrosis marker genes (TGF-β1, α-smooth muscle actin) and a subunit of nuclear factor-ĸB (p65), and attenuated a cellular senescence marker, senescence-associated β-galactosidase activity. Conclusions: Stat3 is involved in Indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence in proximal tubular cells.