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Abstract: SA-PO313

A Role for Toll-Like Receptors and Their Endogenous Ligands in CKD-Associated Cardiovascular Disease?

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Author

  • Raby, Anne-Catherine, Cardiff University, Cardiff, United Kingdom

Group or Team Name

  • Wales Kidney Research Unit
Background

Cardiovascular disease (CVD) is greatly precipitated by chronic kidney disease (CKD). Overall, there is an approximately 20-fold increase in CVD mortality among CKD patients on dialysis compared with the general population. Traditional risk factors do not account for the high cardiovascular risk in CKD and standard clinical interventions are not always effective. CKD specific factors, such as anaemia, mineral metabolism disorders and the presence of uremic toxins are believed to be partially responsible. The inflammation associated with kidney tissue damage or the dialysis process has been suggested to play a substantial role in the onset and progression of CVD, however, it has yet to be demonstrated and the mechanisms elucidated.
Kidney damage has been shown to lead to the local production of Damage Associated Molecular Patterns (DAMPs) that act as endogenous ligands of TLRs. We hypothesise that the TLR DAMPs being generated during CKD reach the circulation where they engage TLRs on the peripheral leukocytes and/or endothelial cells, inducing chronic vascular inflammation and dysfunction that promotes and/or accelerates CVD development.

Methods

Combination of ex vivo, in vitro and in vivo techniques

Results

A range of known TLR DAMPs were quantified in plasma from stage 5 CKD patients (n=40) at the start of PD and compared to the levels found in healthy individuals (n=30). Heat-shock protein (Hsp) 60, Hsp70, hyaluronic acid and calprotectin (S100A8/S100A9) were found significantly elevated in CKD patients. In vitro experiments were conducted to assess the ability of each of these TLR DAMPs to affect cellular responses related to initiation and progression of atherosclerosis. (expression of adhesion molecules by endothelial cells and monocytes, production of cytokines and chemokines, phagocytosis of oxidised LDL by macrophages). In preliminary in vivo experiments, chronic kidney injury was induced by repeated administration of the nephrotoxin aristolochic acid in mice prone to CVD development (LDL receptor deficient) to confirm the findings made in vitro and ex vivo.

Conclusion

Our preliminary results reveal significantly increased levels of several known TLR DAMPs in plasma from patients with late stage CKD. In ongoing work the role that these DAMPs and their interaction with TLRs may play in initiating or worsening atherosclerosis development is being investigated.

Funding

  • Government Support - Non-U.S.