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Indoxyl Sulfate Activates NLRP3 Inflammasome to Induce Cardiac Contractile Dysfunction Accompanied by Myocardial

Kazutoshi Yamaguchi1, Maimaiti Yisireyili1, Sumie Goto2

  • 1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Cardiovascular Toxicology
|January 28, 2022
PubMed

Insights

High indoxyl sulfate (IS) levels in chronic kidney disease (CKD) patients worsen heart failure. This study shows IS directly causes cardiac fibrosis and dysfunction in rats by activating the NLRP3 inflammasome pathway.

Area of Science:

  • Nephrology
  • Cardiology
  • Molecular Biology

Background:

  • High serum indoxyl sulfate (IS) is linked to cardiac fibrosis and hypertrophy in chronic kidney disease (CKD) patients, posing a significant heart failure risk.
  • Uremic cardiomyopathy is a serious complication in CKD patients, characterized by cardiac dysfunction and structural changes.

Purpose of the Study:

  • To investigate the direct effects of indoxyl sulfate (IS) on cardiac function and the inflammasome pathway in a rat model of CKD.
  • To elucidate the molecular mechanisms by which IS impacts myocardial structure and function, independent of renal function and blood pressure.

Main Methods:

  • Utilized Dahl salt-sensitive (DS) and hypertensive (DH) rats, with a DH group treated with IS (DH+IS).
  • Assessed cardiac function (ejection fraction, dilatation), myocardial fibrosis, and hypertrophy using histological and molecular analyses (RT-PCR, Western blotting).
  • Investigated the activation of aryl hydrocarbon receptor (AHR), NF-κB p65, and NLRP3 inflammasome components (NLRP3, ASC, procaspase-1) and inflammatory cytokines (IL-1β, IL-18, MCP-1, TNF-α, IL-6, TGFβ1).

Main Results:

  • DH+IS rats exhibited impaired left ventricular (LV) ejection fraction, LV dilatation, and advanced myocardial fibrosis and hypertrophy, mimicking uremic cardiomyopathy.
  • IS upregulated fibrosis, hypertrophy, and adhesion molecule markers in the heart, independent of renal function and blood pressure.
  • IS activated the AHR/NF-κB pathway, leading to NLRP3 inflammasome activation and increased production of pro-inflammatory cytokines (IL-1β, IL-18, MCP-1, TNF-α, IL-6, TGFβ1).

Conclusions:

  • Indoxyl sulfate directly induces cardiac fibrosis, hypertrophy, and LV dysfunction in a rat model.
  • The cardiac damage mediated by IS is primarily through the activation of the cardiac NLRP3 inflammasome via the AHR/NF-κB signaling pathway.
  • These findings highlight IS as a key mediator of cardiotoxicity in CKD and suggest potential therapeutic targets.

Keywords:
Indoxyl sulfateInflammasomeInflammatory cytokineUremic cardiomyopathy

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