Transcriptome Profiling Reveals Indoxyl Sulfate Should Be Culpable of Impaired T Cell Function in Chronic Kidney Disease

Abstract

Introduction: Chronic inflammation and immune system dysfunction have been evaluated as major factors in the pathogenesis of chronic kidney disease (CKD), contributing to the high mortality rates observed in these populations. Uremic toxins seem to be the potential "missing link." Indoxyl sulfate (IS) is one of the protein-bound renal toxins. It participates in multiple pathologies of CKD complications, yet its effect on immune cell has not been studied. This study aimed to explore the genome-wide expression profile in human peripheral blood T cells under stimulation by IS. Methods: In this study, we employed RNA-sequencing transcriptome profiling to identify differentially expressed genes (DEGs) responding to IS stimulation in human peripheral T cells in vitro. Flow cytometry and western blot were used to verify the discovery in RNA-sequencing analysis. Results: Our results yielded a total of 5129 DEGs that were at least twofold up-regulated or down-regulated significantly by IS stimulation and half of them were concentration-specific. Analysis of T cell functional markers revealed a quite different transcription profile under various IS concentration. Transcription factors analysis showed the similar pattern. Aryl hydrocarbon receptor (AhR) target genes CYP1A1, CYP1B1, NQO1, and AhRR were up-regulated by IS stimulation. Pro-inflammatory genes TNF-α and IFN-γ were up-regulated as verified by flow cytometry analysis. DNA damage was induced by IS stimulation as confirmed by elevated protein level of p-ATM, p-ATR, p-BRCA1, and p-p53 in T cells. Conclusion: The toxicity of IS to T cells could be an important source of chronic inflammation in CKD patients. As an endogenous ligand of AhR, IS may influence multiple biological functions of T cells including inflammatory response and cell cycle regulation. Further researches are required to promulgate the underling mechanism and explore effective method of reserving T cell function in CKD.

Stem/progenitor cell in kidney: characteristics, homing, coordination, and maintenance

“…As an antigenpresenting cell, dendritic cells would induce T cell proliferation and migration to inspire the immune response [185]. T cells, especially CD4 + -T cells, are an important source to persist inflammation in CKD patients [16,186,187]. Abnormal activation of T cells leads to a release of proinflammatory cytokines such as TNF-α and IFN-γ [186], which play an important role in the recruitment of BMSCs [138][139][140].…”

“…T cells, especially CD4 + -T cells, are an important source to persist inflammation in CKD patients [16,186,187]. Abnormal activation of T cells leads to a release of proinflammatory cytokines such as TNF-α and IFN-γ [186], which play an important role in the recruitment of BMSCs [138][139][140]. B cells may also play a role in kidney injury.…”

Indoxyl Sulfate Elevated Lnc-SLC15A1-1 Upregulating CXCL10/CXCL8 Expression in High-Glucose Endothelial Cells by Sponging MicroRNAs

“…It has been reported that the serum levels of IP-10 and IL-8 in diabetic patients are higher than in healthy subjects [58,59]. In addition, research revealed that CXCL10 and CXCL8 are generated by stimulation with the uremic toxin IS [6,60]. In our investigation, mRNA and protein levels of CXCL10 and CXCL8 in HUVECs overexpressing lnc-SLC15A1-1 were escalated and actively secreted to the extracellular space as proteins significantly increased in conditioned medium (Figure 5E,F).…”

“…Accumulating evidence has indicated that the immunopathological and inflammatory cascades play an important role in the initiation and development of CVD [2]. Chronic inflammation and immune system dysfunction are characteristic of DM and can produce a plethora of cytokines and chemokines, thereby contributing to CVD events [3][4][5][6]. For example, IP-10, encoded by CXCL10, and IL-8, encoded by CXCL8, belong to the C-X-C chemokine subfamily [7], and the literature is overflowing with evidence regarding their potential roles in causing atherosclerosis [8][9][10].…”

The antifibrotic and anti-inflammatory effects of FZHY prescription on the kidney in rats after unilateral ureteral obstruction

“…AST-120 has been found by other researchers to significantly decrease CD8 + T cells (-33.9% for central memory T cells, and -42.6% for CD8 + naïve T cells), but it does not affect or slightly reduce CD4 + T cells (0 for T helper cell number, and -13.1% for early activated CD4 + T cells) 36 , which are consistent with our findings in this study. The reduced uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, maybe involved in the phenomenon 37 - 40 . However, the exact mechanism of AST-120 exerting its anti-CKD effect still needs further study.…”