Aryl hydrocarbon receptor (AhR) and its endogenous agonist – indoxyl sulfate in chronic kidney disease

Abstract

The indoxyl sulfate (IS, indoxyl sulphate) is the end product of dietary tryptophan degradation by indole pathway and significantly higher serum and tissue concentrations of this compound is observed in patients with impaired renal function. Despite the high albumin binding affinity, the remaining free fraction of IS has a number of biological effects related to the generation of oxidative stress andactivation of signaling pathways related to NF-кB, p53 protein, STAT3, TGF-β and Smad2/3. IS induces the inflammatory process, exerts nephrotoxic activity and is also a factor impairing the cardiovascular system.Its high concentrations are associated with the occurrence of cardiovascular incidents, whose frequency is significantly higher in patients with chronic kidney disease. Evaluation of the mechanisms that underlie the high reactivity of indoxyl sulfate and its biological effects showed that this compound is an agonist of the aryl hydrocarbon receptor (AhR). This receptor plays an important role in maintaining homeostasis Moreover, AhR exerts high transcriptional activity, so ligands of obciążethis receptor may exert different biological effects. The following paper describes the role of indoxyl sulfate as AhR ligand in the context of the excessive accumulation, which appears as one of the symptoms associated with chronic kidney disease.

Gut-derived uremic toxin handling in vivo requires OAT-mediated tubular secretion in chronic kidney disease

“…In addition, several of these probenecid-sensitive uremic solutes possess signaling capacity. For example, indoxyl sulfate can signal through the aryl hydrocarbon receptor (AHR), the activation of which is associated with a number of adverse conditions, including vascular inflammation, the production of reactive oxygen species, and cardiotoxicity (68)(69)(70). Kynurenic acid, which has a role in signaling in the central nervous system, is also an AHR ligand, as well as a ligand of the G protein-coupled receptor 35 (GPR35), which has also been associated with a number of diseases, including hypertension and heart failure (71,72).…”

Uraemic syndrome of chronic kidney disease: altered remote sensing and signalling

“…Movement of indoxyl sulfate into these cells is probably mediated by OAT3 and other transporters 75 . Moreover, AHR (to which indoxyl sulfate binds 67,76 ) regulates the expression of members of the cytochrome P450 family, other DMEs and transporters 77,78 . At concentrations observed in the serum of patients with uremia, indoxyl sulfate activates expression of CYP1A1, CYP1A2 and CYP1B1 genes, as well as expression of UGT1A1 and UGT1A6 (encoding the phase 2 DMEs UDP-glucuronosyltransferase 1–1 and UDP-glucuronosyltransferase 1–6, respectively) in primary human hepatocytes 69,76 .…”

Association between uremic toxin-anthranilic acid and fibrinolytic system activity in predialysis patients at different stages of chronic kidney disease

“…In a renal-induced hypertension rat model, the plasma levels of AA were associated with increased blood pressure and seemed to be involved in CVD progression [ 17 ]. The renin–angiotensin–aldosterone system (RAAS) plays an important role in maintaining balance of the circulatory system during CKD and its activity is affected by elevated levels of Trp-derived uremic toxins [ 18 , 19 ]. Moreover, the main metabolite of AA-3-hydroxyanthranilic acid has been found to be independently associated with monocyte chemoattractant protein-1 (CCL2) and macrophage inflammatory protein-1beta (CCL4) in CKD patients [ 20 ].…”