indoxyl-glucuronide and Renal-Insufficiency--Chronic

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in the expression of xenobiotic-metabolizing enzymes, inflammatory cytokines and adhesion molecules. Uremic toxins such as indoxyl sulfate and indole acetic acid are derived from tryptophan fermentation by gut microbiota; they accumulate in patients with chronic kidney disease (CKD) on haemodialysis and have recently emerged as potent ligands of AhR. Therefore, AhR can serve as a mediator in inflammation and cardiovascular diseases in these patients. This review discusses current data that support a link between AhR activation and uremic toxins from gut microbiota in CKD.

Topics: Animals; Cardiovascular Diseases; Glucuronates; Humans; Indican; Indoleacetic Acids; Indoles; Models, Biological; Receptors, Aryl Hydrocarbon; Renal Insufficiency, Chronic; Toxins, Biological; Tryptophan; Uremia

Renal anemia is common among chronic kidney disease (CKD) patients, and is mainly caused by inadequate erythropoietin (EPO) production from kidneys due to dysfunction of intracellular hypoxia-inducible factor (HIF) signaling in renal EPO-producing cells. We have previously shown that indoxyl sulfate (IS), a representative protein-bound uremic toxin accumulated in the blood of CKD patients, inhibits hypoxia-induced HIF activation and subsequent EPO production through activation of aryl hydrocarbon receptor (AHR). In this study, we further investigated the effects of other protein-bound uremic toxins on HIF-dependent EPO expression using EPO-producing HepG2 cells. We found that indoxyl glucuronide (IG) and IS, but not p-cresyl sulfate, phenyl sulfate, 3-indoleacetic acid or hippuric acid, inhibited hypoxia mimetic cobalt chloride-induced EPO mRNA expression. Furthermore, IG at concentrations similar to the blood levels in CKD patients inhibited the transcriptional activation of HIF induced by both cobalt chloride treatment and hypoxic culture. IG also induced CYP1A1 mRNA expression and nuclear translocation of AHR protein, indicating that IG activates AHR signaling. Blockade of AHR by a pharmacological antagonist CH-223191 abolished the IG-induced inhibition of HIF activation. Collectively, this study is the first to elucidate the biological effects of IG to inhibit HIF-dependent EPO production through activation of AHR. Our data suggests that not only IS but also IG contributes to the impairment of HIF signaling in renal anemia.

Topics: Cell Survival; Cytochrome P-450 CYP1A1; Erythropoietin; Gene Expression Regulation; Glucuronates; Hep G2 Cells; Humans; Indican; Indoles; Protein Binding; Receptors, Aryl Hydrocarbon; Renal Insufficiency, Chronic; Signal Transduction; Transcriptional Activation; Uremia

Chronic kidney disease (CKD) is characterized by the accumulation of uremic solutes; however, little is known about how these solutes affect drug absorption and disposition. The goal of this study is to evaluate the effect of uremic solutes on the organic cation transporter, OCT2, which plays a key role in the renal secretion of many basic drugs. As a second goal, we reviewed the literature to determine whether there was evidence for the effect of CKD on the renal secretion of basic drugs. We first screened 72 uremic solutes as inhibitors of [

Topics: Biological Transport; Dimethylamines; Glomerular Filtration Rate; Glucuronates; Glutathione Disulfide; HEK293 Cells; Homocysteine; Humans; Indoles; Kidney; Malondialdehyde; Metformin; Methylamines; Organic Cation Transporter 2; Renal Insufficiency, Chronic; Toxins, Biological; Uremia