Chronlc kidney disease (CKD) affects 10-16% ofthe global population. This condition is associated with an enormous burden of complications, including cardiovascular disease (CVD). The biology underlying this relationship is unclear, but may be partly related to pro-atherogenic changes in plasma lipids. Abnormalities in high-density lipoprotein (HDL) are of particular interest because of the well known inverse relationship between HDL cholesterol (HDL-C) and CVD. However, recent efforts to raise HDL-C have failed to show CV benefits in controlled trials, suggesting that HDL function may instead need to be targeted. Indeed, the protective actipn of HDL encompasses reverse cholesterol transport, anti-inflammatory, anti-oxidant, and microRNA (miRNA) transport properties. Loss of function for each of these properties renders HDL less protective or even pro-atherosclerotic. There is little data on how CKD alters the function of HDL or of cellular cholesterol transporters, and on whether severity of CKD affects these processes. Our recently published results provide new insights into the HDL of patients with extreme CKD (end stage renal disease on hemodialysis, ESRD-HD). These HDL showed markedly impaired cholesterol efflux and anti-inflammatory capacities. In addition, pharmacologic activation of cellular transporters improved cholesterol efflux to the dysfunctional HDL of ESRD. These observations are relevant to our findings that monocytes isolated from ESRD have reduced expression of ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor-BI (SR-BI), and that HDL of ESRD down-regulates macrophage ABCA1 expression. Interestingly, ABCAI expression is also regulated by miRNAs and isolevuglandins (IsoLG, highly reactive products of lipid peroxidation) carried by HDL. We show that HDL of ESRD is enriched in IsoLG and that HDL enrichment in IsoLG impacts its capacity to accept the miRNAs that convey anti-inflammatory properties. We also show that the uremic HDL has an abnormal miRNA profile and an impaired capacity to deliver miRNAs to recipient cells. These observations led us to hypothesize that kidney disease results in multiple deficiencies in HDL function and disruption of cellular cholesterol transporters that are inversely related to CKD severity. We speculate that CKD promotes accumulation of IsoLG in, and alters the miRNA profile of HDL. These studies will help development of biomarkers for impaired HDL function and provide a new direction for development of therapeutic strategies to improve dysfunctional HDL and provide CV protection to patients with CKD.
): Although chronic kidney disease (CKD) increases the risk of heart attack and stroke, the reasons for this association are unknown. HDL, which provides important cardiovascular protection, appears dysfunctional in CKD. Our focus is to determine the mechanisms underlying CKD-induced impairment in HDL and its receptors that may lead to development of new therapeutic strategies in patients with CKD as well as cardiovascular disease in the general population.
|Babaev, Vladimir R; Hebron, Katie E; Wiese, Carrie B et al. (2014) Macrophage deficiency of Akt2 reduces atherosclerosis in Ldlr null mice. J Lipid Res 55:2296-308|
|Vickers, Kasey C; Landstreet, Stuart R; Levin, Michael G et al. (2014) MicroRNA-223 coordinates cholesterol homeostasis. Proc Natl Acad Sci U S A 111:14518-23|
|Allen, Ryan M; Vickers, Kasey C (2014) Coenzyme Q10 increases cholesterol efflux and inhibits atherosclerosis through microRNAs. Arterioscler Thromb Vasc Biol 34:1795-7|