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Uremic toxins activate CREB/ATF1 in endothelial cells related to chronic kidney disease

Regiane Stafim da Cunha1, Paulo Cézar Gregório1, Rayana Ariane Pereira Maciel1

  • 1Experimental Nephrology Laboratory, Basic Pathology Department, Universidade Federal do Paraná, Curitiba, PR, Brazil.

Biochemical Pharmacology
|March 4, 2022
PubMed

Insights

Uremic toxins like p-cresyl sulfate and indoxyl sulfate activate cAMP-responsive element-binding protein (CREB) and activating transcription factor 1 (ATF1) in endothelial cells. This activation contributes to endothelial dysfunction in chronic kidney disease (CKD).

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Uremic toxins, including p-cresyl sulfate (PCS) and indoxyl sulfate (IS), are implicated in endothelial dysfunction in chronic kidney disease (CKD).
  • The roles of cAMP-responsive element-binding protein (CREB) and activating transcription factor 1 (ATF1) in uremic endothelial dysfunction are not fully understood, despite their involvement in inflammatory pathways.

Purpose of the Study:

  • To investigate the expression, activation, and transcriptional activity of CREB and ATF1 in endothelial cells exposed to uremic toxins.
  • To determine the potential involvement of CREB/ATF1 in the endothelial dysfunction associated with CKD.

Main Methods:

  • In vitro exposure of endothelial cells to PCS, IS, and uremic serum (US).
  • Assessment of CREB and ATF1 protein levels, phosphorylation (activation), and transcriptional activity of target genes (ICAM1, PTGS2, NOX1, SLC22A6).
  • Inhibition of CREB using KG-501 to evaluate its role in toxin-induced gene expression.

Main Results:

  • PCS and IS increased ATF1 protein levels; IS also increased CREB levels.
  • PCS, IS, and US induced CREB-Ser133 and ATF1-Ser63 phosphorylation.
  • Uremic toxins upregulated inflammatory and oxidative stress genes (ICAM1, PTGS2, NOX1), with IS also affecting SLC22A6.
  • CREB inhibition partially reversed the effects of uremic toxins on target gene expression.

Conclusions:

  • CREB and ATF1 are activated by uremic toxins (PCS, IS, US) in endothelial cells.
  • Activated CREB/ATF1 signaling contributes to endothelial dysfunction in CKD by modulating inflammatory and oxidative stress pathways.
  • CREB/ATF1 represents a potential therapeutic target for mitigating endothelial dysfunction in CKD.
Keywords:
ATF1CREBEndothelium dysfunctionIndoxyl sulfatep-cresyl sulfate

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