Indoxyl sulfate counteracts endothelial effects of erythropoietin through suppression of Akt phosphorylation.
(65/86)
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. (+info)
Reduction of indoxyl sulfate by AST-120 attenuates monocyte inflammation related to chronic kidney disease.
(66/86)
Molecular mechanisms for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection.
(71/86)
Chronic kidney disease (CKD), marked by a progressive loss in renal function, is a leading cause of hemodialysis initiation and cardiovascular disease (CVD). There are currently 13.3 million patients with CKD and 300 thousand patients are currently undergoing hemodialysis in Japan. Therefore, preventing the initiation of dialysis and reducing the risk of cardiovascular death are high-priority issues from the viewpoint of public health and economic implications. Understanding the molecular mechanism responsible for the progression of CKD and cardiovascular damage regarding crosstalk between the kidney and cardiovascular system is an important issue in controlling the pathogenesis of CKD-CVD. However, the mechanisms involved in CKD-CVD are not well understood. This hinders the development of new treatment strategies. We have been investigating the role of protein bound uremic toxins, that are difficult to remove by hemodialysis, on the onset and progression of CKD and CVD. The relationship between their redox properties and the pathogenesis of CKD-CVD was examined. In this review, we focus on two sulfate conjugated uremic toxins, namely, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), and summarize recent studies that provide new insights on the molecular mechanisms responsible for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection. (+info)
Effects of decreased vitamin D and accumulated uremic toxin on human CYP3A4 activity in patients with end-stage renal disease.
(72/86)