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Tryptophan Metabolites Target Transmembrane and Immunoglobulin Domain-Containing 1 Signaling to Augment Renal Tubular

Mostafa Belghasem1, Wenqing Yin2, Saran Lotfollahzadeh2

  • 1Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts.

The American Journal of Pathology
|September 7, 2023
PubMed

Insights

Tryptophan toxins like indoxyl sulfate and kynurenine harm kidney tubules by reducing TMIGD1. Loss of TMIGD1 worsens chronic kidney disease (CKD) in mice, revealing a new tubulotoxicity mechanism.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Toxicology

Background:

  • Chronic kidney disease (CKD) involves uremic toxin accumulation and tubular damage.
  • Tryptophan-derived toxins, indoxyl sulfate (IS) and kynurenine (Kyn), are known tubulotoxins.
  • Transmembrane and immunoglobulin domain-containing 1 (TMIGD1) is suggested to protect tubular cells.

Purpose of the Study:

  • To investigate the molecular crosstalk between IS/Kyn and TMIGD1 in tubular toxicity.
  • To determine if IS and Kyn mediate toxicity via TMIGD1 and if TMIGD1 loss exacerbates kidney injury.

Main Methods:

  • Assessed TMIGD1 transcription suppression by IS and Kyn in tubular cells.
  • Utilized reporter assays to evaluate the role of CCAAT enhancer-binding protein β (C/EBPβ) in TMIGD1 regulation.
  • Examined TMIGD1 and C/EBPβ expression in various CKD mouse models.
  • Investigated the effects of TMIGD1 inactivation in mice on renal function and tubular integrity.

Main Results:

  • IS and Kyn suppressed TMIGD1 transcription dose-dependently.
  • C/EBPβ positively regulated TMIGD1 promoter activity, while IS reduced C/EBPβ levels.
  • Reduced TMIGD1 expression correlated with C/EBPβ levels and increased IS/Kyn in CKD models.
  • TMIGD1 inactivation in mice led to severe tubular damage, reduced proliferation, and impaired renal function.

Conclusions:

  • TMIGD1 protects renal tubular cells against injury in multiple CKD models.
  • Tryptophan-derived uremic toxins (IS and Kyn) induce tubulotoxicity by suppressing TMIGD1 via C/EBPβ.
  • This study uncovers a novel molecular mechanism for tryptophan-based uremic tubulotoxicity in CKD.

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