Dysfunctional high-density-lipoprotein (d-HDL) in chronic kidney disease

Patients with chronic kidney disease (CKD) exhibit endothelial dysfunction and accelerated vascular disease leading to increased morbidity and mortality due to cardiovascular events. The underlying mechanisms, however, are still not fully understood. Traditional cardiovascular disease (CVD) risk factors such as hypertension and hyperlipidemia do not adequately explain the high prevalence of CVD in CKD. Both CVD and CKD are inflammatory states and inflammation adversely affects lipid balance. Dyslipidemia in CKD is characterized by elevated triglyceride levels and high-density lipoprotein levels that are both decreased and dysfunctional. This dysfunctional high-density lipoprotein (d-HDL) becomes proinflammatory and loses its atheroprotective ability to promote cholesterol efflux from cells, including lipid-overloaded macrophages in the arterial wall. Recently, we started investigating the potential endothelial-damaging effects of d-HDL from CKD patients. Specifically, we identify and characterize different endothelial-damaging agents that accumulate in HDL in CKD, such as symmetric-dimethyl-arginine (SDMA), which is amongst other effects known to reduce endothelial nitric-oxide (NO) availability. We are investigating intracellular signaling pathways activated by these agents leading to endothelial activation and damage. Understanding these molecular mechanisms might help to develop new therapeutic approaches to reduce the accelerated atherosclerosis in CKD patients, which suffer from multiple cardiovascular complications.

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