Indoxyl sulfate contributes to colorectal cancer cell proliferation and increased EGFR expression by activating AhR and Akt.

Although patients with chronic kidney disease (CKD) have a higher risk of colorectal cancer (CRC) aggravation, the connection between these two diseases is not well understood. Recent studies have shown that both CKD and CRC aggravation are closely related to an increased abundance of indole-producing Fusobacterium nucleatum in the gut. The indole absorbed from the gut is eventually metabolized to indoxyl sulfate in the liver.

Indoxyl Sulfate Activates NLRP3 Inflammasome to Induce Cardiac Contractile Dysfunction Accompanied by Myocardial Fibrosis and Hypertrophy.

In patients with chronic kidney diseases (CKD), high serum indoxyl sulfate (IS) levels correlate with cardiac fibrosis and hypertrophy and thus a critical risk factor for heart failure. The aim of this study was to determine the effects of IS on cardiac function and inflammasome pathway in a rat model of CKD. We assessed the physiological and pathological changes and measured biomarkers of fibrosis and hypertrophy in the hearts of Dahl salt-sensitive (DS), DS hypertensive (DH), and DH IS-treated rats (DH + IS).

Indoxyl Sulfate-induced Vascular Calcification is mediated through Altered Notch Signaling Pathway in Vascular Smooth Muscle Cells.

The aim of this study was to determine the role of Notch in indoxyl sulfate (IS)-induced vascular calcification (VC). VC and expression of Notch-related and osteogenic molecules were examined in Dahl salt-sensitive (DS), DS hypertensive (DH), and DH IS-treated rats (DH+IS). The effects of IS on expression of Notch receptors, apoptotic activity, and calcification were examined in cultured aortic smooth muscle cells (SMCs).

Effects of the oral adsorbent AST-120 on fecal p-cresol and indole levels and on the gut microbiota composition.

In chronic kidney disease, elevated levels of circulating uremic toxins are associated with a variety of symptoms and organ dysfunction. Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are microbiota-derived metabolites and representative uremic toxins. We have previously shown that the oral adsorbent AST-120 profoundly reduced pCS compared to IS in adenine-induced renal failure in mice.

Impact of the Oral Adsorbent AST-120 on Organ-Specific Accumulation of Uremic Toxins: LC-MS/MS and MS Imaging Techniques.

Elevated circulating uremic toxins are associated with a variety of symptoms and organ dysfunction observed in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS) and -cresyl sulfate (PCS) are representative uremic toxins that exert various harmful effects. We recently showed that IS induces metabolic alteration in skeletal muscle and causes sarcopenia in mice.

Indole-3-propionic acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory genes in proximal tubular cells.

Indoxyl sulfate (IS) induces fibrosis and inflammation in kidneys via oxidative stress through the induction of transforming growth factor-β1 (TGF-β1) and monocyte chemotactic protein-1 (MCP-1). Furthermore, IS is a potent endogenous agonist for aryl hydrocarbon receptor (AHR), which regulates the transcription of genes such as cytochrome P450 (CYP) 1A1. Indole-3-propionic acid (IPA) is an antioxidant and has been reported to be neuroprotective.

Influence of AHRR Pro189Ala polymorphism on kidney functions.

The function of aryl hydrocarbon receptor repressor (AHRR) in the kidney is unclear. The present study investigated associations between AHRR Pro189Ala polymorphism and estimated glomerular filtration rates (eGFR), serum creatinine, and hemoglobin levels in 2775 Japanese adults without diabetes. In addition, we examined whether AHRR expression levels in the kidney of control and chronic kidney disease (CKD) rats were changed.

Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice.

Chronic stress is closely linked to the metabolic syndrome, diabetes, hyperuricemia and thromboembolism, but the mechanisms remain elusive. We reported recently that stress targets visceral adipose tissue (VAT), inducing lipolysis, low-grade inflammation with production of inflammatory adipokines, metabolic derangements such as insulin resistance, and prothrombotic state. In the present study, we hypothesized the involvement of VAT xanthine oxidoreductase (XOR), a source of reactive oxygen species (ROS) and uric acid (UA) in the above processes.

The role of carbon adsorbent in the conservative management of chronic kidney disease.

Indoxyl sulfate is a uremic toxin, and cannot be removed efficiently by hemodialysis due to its protein-binding. Indoxyl sulfate induces cellular dysfunction by producing reactive oxygen species (ROS) such as superoxide by activating nicotinamide adenine dinucleotide phosphate oxidase, and by activating aryl hydrocarbon receptor through its uptake via organic anion transporters (OAT1 and OAT3). Indoxyl sulfate shows toxic effects on a variety of cells such as renal proximal tubular cells, glomerular mesangial cells, vascular smooth muscle cells, vascular endothelial cells, cardiomyocytes, cardiac fibroblasts, monocytes, osteoblasts, osteoclasts, and myocytes.

Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease.

Sarcopenia is associated with increased morbidity and mortality in chronic kidney disease (CKD). Pathogenic mechanism of skeletal muscle loss in CKD, which is defined as uremic sarcopenia, remains unclear. We found that causative pathological mechanism of uremic sarcopenia is metabolic alterations by uremic toxin indoxyl sulfate.

Genotype frequencies for polymorphisms related to chemotherapy-induced nausea and vomiting in a Japanese population.

Background: Genotype frequencies for chemotherapy-induced nausea and vomiting (CINV)-related polymorphisms have not yet been reported for Japanese subjects.

Methods: We analyzed 10 genotype frequencies for following polymorphisms associated with the development of CINV: serotonin 5-HT3 receptors (HTR3); neurokinin-1 receptors (Tachykinin-1 receptors, TACR1); dopamine D2 receptors (DRD2); and catechol-O-methyltransferase (COMT).

Results: All polymorphisms were successfully genotyped in 200 Japanese subjects and were in Hardy-Weinberg equilibrium.

Indoxyl Sulfate Downregulates Mas Receptor via Aryl Hydrocarbon Receptor/Nuclear Factor-kappa B, and Induces Cell Proliferation and Tissue Factor Expression in Vascular Smooth Muscle Cells.

Background/aim: Angiotensin converting enzyme-related carboxypeptidase 2/angiotensin (Ang)-(1-7)/Mas receptor axis is protective in the development of chronic kidney disease and cardiovascular disease. This study is aimed at investigating whether indoxyl sulfate (IS) affects Mas receptor expression, cell proliferation and tissue factor expression in vascular smooth muscle cells, and if Ang-(1-7), an activator of Mas receptor, counteracts the IS-induced effects.

Methods: IS was administered to normotensive and hypertensive rats.

Indoxyl sulfate upregulates prorenin expression via nuclear factor-κB p65, signal transducer and activator of transcription 3, and reactive oxygen species in proximal tubular cells.

We have recently found that indoxyl sulfate induces prorenin expression in proximal tubular cells. The present study aimed to determine whether nuclear factor-κB (NF-κB) p65, signal transducer and activator of transcription 3 (Stat3), and reactive oxygen species are involved in indoxyl sulfate-induced prorenin expression in cultured human proximal tubular cells (HK-2 cells). Effects of indoxyl sulfate on prorenin expression were determined using HK-2 cells with small interfering RNAs (siRNAs) specific to NF-κB p65 and Stat3, N-acetylcysteine, an antioxidant, and diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase.

Indoxyl sulfate induces IL-6 expression in vascular endothelial and smooth muscle cells through OAT3-mediated uptake and activation of AhR/NF-κB pathway.

Background/aims: Interleukin-6 (IL-6) is one of the inflammation biomarkers with highest predictive value for outcome in chronic kidney disease (CKD) patients. The present study aimed to determine the effects of indoxyl sulfate (IS) on IL-6 expression in vascular cells.

Methods: IS was administered to normo- and hypertensive rats.

Indoxyl sulfate-induced activation of (pro)renin receptor promotes cell proliferation and tissue factor expression in vascular smooth muscle cells.

Unlabelled: Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). (Pro)renin receptor (PRR) is activated in the kidney of CKD. The present study aimed to determine the role of indoxyl sulfate (IS), a uremic toxin, in PRR activation in rat aorta and human aortic smooth muscle cells (HASMCs).

Polymorphisms of Nrf2, an antioxidative gene, are associated with blood pressure in Japanese.

Nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant genes by activating Nrf2-antioxidant response element (ARE) pathway. This study aimed to investigate association of Nrf2 gene single nucleotide polymorphisms (SNPs), rs35652124 (A --> G) and rs6721961 (C --> A), with various laboratory data in 464 health evaluation examinees. The genotyping of these SNPs was performed using polymerase chain reaction with confronting two-pair primers (PCR-CTPP) assay.

Plasma indoxyl sulfate and estimated glomerular filtration rate.

Background: Indoxyl sulfate (IS), a uremic toxin, has cardiovascular as well as uremic toxicity. We evaluated the prognostic value of blood IS level for long-term outcome.

Methods And Results: This study followed 311 patients with coronary artery disease.

Polymorphism of Nrf2, an antioxidative gene, is associated with blood pressure and cardiovascular mortality in hemodialysis patients.

Objective: Nrf2 is a transcription factor that regulates the expression of antioxidant genes. This study aimed to investigate the association of Nrf2 gene single nucleotide polymorphisms (SNPs), rs35652124 (-653A/G) and rs6721961 (-617C/A), with laboratory data and mortality in hemodialysis (HD) patients.

Methods: Blood samples were obtained from 216 HD patients (119 males and 97 females; 60 diabetics and 156 non-diabetics) with mean age of 60.

Protein-bound molecules: a large family with a bad character.

Many small solutes excreted by the kidney are bound to plasma proteins, chiefly albumin, in the circulation. The combination of protein binding and tubular secretion allows the kidney to reduce the free, unbound concentrations of such solutes to lower levels than could be obtained by tubular secretion alone. Protein-bound solutes accumulate in the plasma when the kidneys fail, and the free, unbound levels of these solutes increase more than their total plasma levels owing to competition for binding sites on plasma proteins.

Indoxyl sulfate downregulates expression of Mas receptor via OAT3/AhR/Stat3 pathway in proximal tubular cells.

Unlabelled: Renin-angiotensin system (RAS) plays a pivotal role in chronic kidney disease (CKD). Angiotensin converting enzyme-related carboxypeptidase 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor axis counteracts the deleterious actions of Ang II. ACE2 exerts its actions by cleaving Ang II into Ang-(1-7) which activates Mas receptor.

Indoxyl sulfate-induced activation of (pro)renin receptor is involved in expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells.

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.

AST-120 for the management of progression of chronic kidney disease.

Uremic toxins such as indoxyl sulfate contribute to the pathogenesis of chronic kidney disease (CKD) by promoting glomerulosclerosis and interstitial fibrosis with loss of nephrons and vascular damage. AST-120, an orally administered intestinal sorbent, adsorbs indole, a precursor of indoxyl sulfate, thereby reducing serum and urinary concentrations of indoxyl sulfate. AST-120 has been available in Japan since 1991, and subsequently Korea (2005), and the Philippines (2010) as an agent to prolong the time to initiation of hemodialysis and for improvement of uremic symptoms in patients with CKD.