Indoxyl sulfate counteracts endothelial effects of erythropoietin through suppression of Akt phosphorylation.

Abstract

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. 

• Authors: Yelixiati Adelibieke, Hidehisa Shimizu, Shinichi Saito, Roumyana Mironova, Toshimitsu Niwa
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 77 Issue 5 Pg. 1326-36 ( 2013) ISSN: 1347-4820 [Electronic] Japan
• PMID: 23337206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• EPO protein, human
• Protein Kinase Inhibitors
• Receptors, Erythropoietin
• Thrombospondin 1
• Erythropoietin
• NOS3 protein, human
• Nitric Oxide Synthase Type III
• Proto-Oncogene Proteins c-akt
• Indican

Topics

• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Erythropoietin (pharmacology)
• Human Umbilical Vein Endothelial Cells (drug effects, enzymology)
• Humans
• Indican (pharmacology)
• Nitric Oxide Synthase Type III (metabolism)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• RNA Interference
• Receptors, Erythropoietin (drug effects, metabolism)
• Signal Transduction (drug effects)
• Thrombospondin 1 (metabolism)
• Time Factors
• Transfection