Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall

Area of Science:

• Nephrology
• Cardiovascular Research
• Immunology

Background:

• Cardiovascular disease (CKD) is a leading cause of death in patients with chronic kidney disease (CKD).
• Leukocyte activation and endothelial damage are key contributors to cardiovascular complications in CKD.
• Uremic toxins, particularly protein-bound solutes, are implicated in inflammation and vascular injury, but their direct impact on leukocyte-endothelial crosstalk in vivo is not well understood.

Purpose of the Study:

• To investigate the in vivo effects of specific uremic toxins—indoxyl sulfate (IS), p-cresylsulfate (pCS), and p-cresylglucuronide (pCG)—on leukocyte recruitment and vascular responses.
• To elucidate the mechanisms underlying the pro-inflammatory and vascular damaging effects of these toxins.

Main Methods:

• Utilized intravital microscopy in a rat peritoneal model to observe leukocyte-endothelial interactions under superfusion and intravenous infusion of uremic toxins.
• Assessed leukocyte adhesion, extravasation, rolling, and blood flow dynamics.
• Measured heparan sulfate shedding as an indicator of glycocalyx disruption.

Main Results:

• Indoxyl sulfate (IS) induced significant leukocyte adhesion, extravasation, and blood flow interruption.
• p-Cresylsulfate (pCS) rapidly increased leukocyte rolling, while combined pCS and p-cresylglucuronide (pCG) impaired blood flow and caused vascular leakage.
• IS infusion led to heparan sulfate shedding, suggesting glycocalyx disruption as a mechanism for flow stagnation.

Conclusions:

• This study provides the first in vivo evidence that IS, pCS, and pCG promote inflammation and vascular damage.
• These uremic toxins stimulate crosstalk between leukocytes and the vasculature, contributing to cardiovascular pathology in CKD.
• Disruption of the endothelial glycocalyx by IS is a likely mechanism mediating its adverse vascular effects.