Abstract
Protein-bound uremic toxin is a cardiovascular (CV) risk factor for patients with end-stage renal disease. Indole-3-acetic acid (IAA) was found to be associated with CV disease but the detailed pathophysiology remains unknown. Moreover, mitogen-activated protein kinase (MAPK) signaling cascades play an important role in the pathogenesis of CV disease. Thus, we explored the association between circulating IAA levels and forty MAPK cascade associated proteins in patients undergoing hemodialysis (HD). Circulating total form IAA was quantified by mass spectrometry and forty MAPK cascade associated proteins by a proximity extension assay in 331 prevalent HD patients. Accounting for multiple testing, and in multivariable-adjusted linear regression models, circulating total form IAA levels were positively associated with stem cell factor (β coefficient 0.13, 95% confidence interval 0.04 to 0.21, p = 0.004). A bioinformatics approach using the search tool for interactions of chemicals (STITCH) tool provided information that IAA may be involved in the regulation of cell proliferation, hematopoietic cells, and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. The knowledge gained here can be generalized, thereby impacting the non-traditional CV risk factors in patients with kidney disease. Further in vitro work is necessary to validate the translation of the mechanistic pathways.
Highlights
Cardiovascular (CV) disease is the leading cause of death in patients with chronic kidney disease [1,2]
341 HD patients were enrolled and mitogen-activated protein kinase (MAPK) cascade associated proteins were measured by proximity extension assays
The association between total Indole-3-acetic acid (IAA) level and forty MAPK cascade associated proteins was analyzed in 331 HD patients (Figure 1)
Summary
Cardiovascular (CV) disease is the leading cause of death in patients with chronic kidney disease [1,2]. The accumulation of indoxyl sulfate (IS), which is the most well-investigated protein-bound uremic toxin, can cause vascular dysfunction in experimental animals and humans with CKD [6,7,8,9]. IAA mediated oxidative stress by increasing reactive oxygen species (ROS) production and increased the expression of inflammatory genes (interleukin-6 (IL-6), interleukin-8 (IL-8), intracellular adhesion molecule 1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1)) in endothelial cells [13]. We hypothesized that IAA may correlate with proteins that triggered MAPK cascade and further link CV disease in CKD subjects. The association between circulating IAA level and MAPK cascade associated proteins was investigated in a clinical setting to explore potential new CV signaling in patients undergoing hemodialysis (HD)
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