Role of Gut-Derived Protein-Bound Uremic Toxins in Cardiorenal Syndrome and Potential Treatment Modalities

Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation

“…Moreover, Barreto et al showed that serum indoxyl sulfate progressively increases with stages of chronic kidney disease and is associated with the incidence of cardiovascular disease and overall mortality in patients with chronic kidney disease 12) . Several studies have suggested that indoxyl sulfate aggravates cardiovascular disease by inducing cardiac cell fibrosis, endothelial senescence, proliferation of vascular smooth muscle cells, and activation of monocytes/ macrophages via an oxidative stress-dependent pathway [14][15][16][17][18][19][20][21][22] . In addition, we previously showed that indoxyl sulfate enhances cytokine-induced leukocyteendothelial interactions through E-selectin in vivo and in vitro, and this process is mediated by activation of oxidative stress-dependent intracellular signaling such as JNK and NF-B in human umbilical vein endothelial cells (HUVEC) 23) .…”

Levels of Indoxyl Sulfate in Kidney Transplant Patients, and the Relationship With Hard Outcomes

“…4 A substantial number of studies have linked the concentration of uremic solutes to overall mortality and CVD. [5][6][7][8] Many studies have focused on establishing the circulating concentrations of individual solutes in predialysis and dialysis patients. In contrast, there are very few published data on levels of uremic toxins in kidney transplant patients in general and levels during the first year after transplantation in particular.…”

Gut bacteria-derived molecules as mediators and markers in cardiovascular diseases. The role of the gut-blood barrier

“…In addition, indoxyl was found to stimulate hypertrophy of neonatal rat cardiac myocytes, and production of collagen by neonatal cardiac fibroblasts. In CKD patients, a positive correlation between an increased serum indoxyl sulphate and aortic calcification and vascular stiffness was reported [9,32].…”

“…Indole and its metabolites are thought to be harmful, linked to development of diseases or their progression. Increased plasma indole levels were associated with higher mortality in patients with CKD [9], progression of cardiac fibrosis [32], pro-arrhythmogenic, and prothrombotic effects [9] and were predictive of increased risk of cardiovascular events in CKD [49]. In contrast, SCFA seem to be cardioprotective compounds, with vasodilating and hypotensive potential.…”

“…Heart failure development [48] Indoles Intracellular signalling, biofilm formation, antibiotic resistance in bacteria [30] Accumulation in patients with CKD [9] Impairment of antioxidation and promotion of free radical formation [9] Promotion of endothelium dysfunction: decreased production of nitric oxide, increased production of reactive oxygen species [9] Hypertrophy of cardiac myocytes and production of collagen by cardiac fibroblasts [32] Decrease of indole concentration is beneficial in CKD [31] Correlation of high concentration of indoxyl sulphate with aortic lesion formation and mortality in CKD [9] Pro-arrhythmogenic potential [9] Association with CV events and mortality in CKD [49] Short-chain fatty acids Energy source of colonic cells and pH regulating agents…”