Tryptophan Metabolites Regulate Neuropentraxin 1 Expression in Endothelial Cells

Romain Vial,Stéphane Poitevin,Stéphane Burtey,Nathalie Mckay,Claire Cerini

doi:10.3390/ijms23042369

Abstract

In patients with chronic kidney disease (CKD) and in animal models of CKD, the transcription factor Aryl Hydrocabon Receptor (AhR) is overactivated. In addition to the canonical AhR targets constituting the AhR signature, numerous other genes are regulated by this factor. We identified neuronal pentraxin 1 (NPTX1) as a new AhR target. Belonging to the inflammatory protein family, NPTX1 seems of prime interest regarding the inflammatory state observed in CKD. Endothelial cells were exposed to tryptophan-derived toxins, indoxyl sulfate (IS) and indole-3-acetic acid (IAA). The adenine mouse model of CKD was used to analyze NPTX1 expression in the burden of uremia. NPTX1 expression was quantified by RT-PCR and western blot. AhR involvement was analyzed using silencing RNA. We found that IS and IAA upregulated NPTX1 expression in an AhR-dependent way. Furthermore, this effect was not restricted to uremic indolic toxins since the dioxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) do the same. In CKD mice, NPTX1 expression was increased in the aorta. Therefore, NPTX1 is a new target of AhR and further work is necessary to elucidate its exact role during CKD.

Highlights

Published: 21 February 2022Chronic kidney disease (CKD), affecting 11% of the world’s population, arises from diseases that occur at a variable pace, leading to progressive and irreversible destruction of the kidney [1]
In the presence of indoxyl sulfate (IS), neuronal pentraxin 1 (NPTX1) protein expression followed those of mRNA, with the highest levels reached at 10 h and a progressive return to low levels until 24 h (Figure 1B,C)
We showed that two uremic indolic solutes induced the expression of

Summary

Introduction

Published: 21 February 2022Chronic kidney disease (CKD), affecting 11% of the world’s population, arises from diseases that occur at a variable pace, leading to progressive and irreversible destruction of the kidney [1]. The continuous loss of nephrons during CKD leads to perturbations of the internal environment, which worsen during the progression of the disease. Accumulation of uremic toxins impacts all functions of the body and patients with CKD display numerous health problems, such as anemia, increased bone fragility and cancer risk, cognitive impairment, and gastrointestinal disturbances [1]. Endothelium dysfunction [5,6,7,8,9], chronic inflammation [10,11,12], procoagulant state [10,11,12,13,14,15,16] and uremic toxins [2,8,15,16,17,18] are the new players of CVD associated with CKD

Objectives

Methods

Results

Conclusion