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Updated: Jul 13, 2025
Assessment of Vascular Function in Patients With Chronic Kidney Disease
Published on: June 16, 2014
Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology
Morgane Mazzarino1,2, Esra Cetin1,2, Maria Bartosova3
1Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
Insights
Chronic kidney disease (CKD) drives cardiovascular disease via inflammation. Targeting Damage-Associated Molecular Patterns (DAMPs) and Toll-like Receptors (TLRs) with therapies like Calprotectin blockade shows promise for reducing vascular pathology in CKD patients.
Area of Science:
- Immunology
- Nephrology
- Cardiology
- Molecular Biology
Background:
- Chronic kidney disease (CKD) significantly increases cardiovascular morbidity and mortality, largely driven by chronic inflammation.
- Damage-Associated Molecular Patterns (DAMPs), acting as pro-inflammatory Toll-like Receptor (TLR) agonists, are elevated in CKD and implicated in cardiovascular disease (CVD) pathogenesis.
- The specific roles, mechanisms, and therapeutic targets of DAMPs in CKD-associated vascular pathology remain incompletely understood.
Purpose of the Study:
- To confirm the involvement of DAMPs in CKD-associated vascular inflammation and atherosclerosis.
- To elucidate the underlying mechanisms by which specific DAMPs contribute to vascular pathology.
- To evaluate potential therapeutic strategies targeting the DAMP-TLR pathway for reducing cardiovascular risk in CKD.
Main Methods:
- Administration of a multi-TLR inhibitor (soluble TLR2) in nephropathic mice to assess its impact on vascular inflammation and atherosclerosis.
- Quantification of four specific DAMPs (Hsp70, Hyaluronic acid, HMGB-1, Calprotectin) in CKD patient plasma and assessment of their TLR-dependent effects on vascular cells.
- In vivo blockade of Calprotectin in nephropathic mice to evaluate its therapeutic potential.
Main Results:
- Soluble TLR2 treatment reduced vascular inflammation and atherosclerosis-associated gene expression in mice without impairing infection clearance.
- Four DAMPs were elevated in CKD patients; Calprotectin and Hsp70 most significantly promoted vascular inflammation, monocyte migration, cytokine production, and foam cell formation.
- Calprotectin blockade in mice markedly reduced vascular inflammation and pro-atherosclerotic gene expression, with higher Calprotectin levels correlating with CRP in CKD patients with CVD.
Conclusions:
- The DAMP-TLR pathway critically contributes to vascular inflammation and atherogenesis in CKD.
- Specific DAMPs, particularly Calprotectin and Hsp70, play significant mechanistic roles in promoting vascular pathology.
- Targeting DAMPs, such as through Calprotectin blockade, represents a promising therapeutic strategy to mitigate cardiovascular complications in CKD.
Abstract:
Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR agonists, Damage-Associated Molecular Patterns (DAMPs), have been found elevated in CKD patients' plasma and suggested to promote CVD, however, confirmation of their involvement, the underlying mechanism(s), the extent to which individual DAMPs contribute to vascular pathology in CKD and the evaluation of potential therapeutic strategies, have remained largely undescribed. A multi-TLR inhibitor, soluble TLR2, abrogated chronic vascular inflammatory responses and the increased aortic atherosclerosis-associated gene expression observed in nephropathic mice, without compromising infection clearance. Mechanistically, we confirmed elevation of 4 TLR DAMPs in CKD patients' plasma, namely Hsp70, Hyaluronic acid, HMGB-1 and Calprotectin, which displayed different abilities to promote key cellular responses associated with vascular inflammation and progression of atherosclerosis in a TLR-dependent manner. These included loss of trans-endothelial resistance, enhanced monocyte migration, increased cytokine production, and foam cell formation by macrophages, the latter via cholesterol efflux inhibition. Calprotectin and Hsp70 most consistently affected these functions. Calprotectin was further elevated in CVD-diagnosed CKD patients and strongly correlated with the predictor of CV events CRP. In nephropathic mice, Calprotectin blockade robustly reduced vascular chronic inflammatory responses and pro-atherosclerotic gene expression in the blood and aorta. Taken together, these findings demonstrated the critical extent to which the DAMP-TLR pathway contributes to vascular inflammatory and atherogenic responses in CKD, revealed the mechanistic contribution of specific DAMPs and described two alternatives therapeutic approaches to reduce chronic vascular inflammation and lower CV pathology in CKD.
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