Lipotoxicity and impaired high density lipoprotein-mediated reverse cholesterol transport in chronic kidney disease

Abstract

Chronic kidney disease (CKD) is associated with a high risk of death from cardiovascular disease. Inflammation, oxidative stress, and dyslipidemia, which are common consequences of CKD, contribute to the pathogenesis of atherosclerosis and cardiovascular disease in this population. Dyslipidemia of CKD is characterized by diminished plasma high density lipoprotein (HDL) concentration, impaired HDL anti-oxidant and anti-inflammatory activities, and elevated plasma triglyceride, very low density lipoprotein (VLDL), intermediate density lipoprotein, chylomicron remnants, and oxidized lipids and lipoproteins. The constellation of inflammation, HDL deficiency, and oxidative modification of lipoproteins can cause atherosclerosis and progression of renal disease. We have recently found lipid accumulation in the remnant kidney and the wall of aorta in rats with CKD induced by 5/6 nephrectomy. This was mediated by up-regulation of scavenger receptors involved in the influx of oxidized lipids or lipoproteins, tubular reabsorption of lipid binding proteins through megalin-cubilin complexes, upregulation of fatty acid synthesis, and downregulation of fatty acid oxidation pathways. The combination of increased lipid influx, elevated production and reduced catabolism of lipids, and impaired HDL-mediated reverse cholesterol transport can promote atherosclerosis, glomerulosclerosis, and tubulointerstitial damage. Although statins can be effective in slowing CKD progression in patients with mild-to-moderate CKD, they have consistently failed to mitigate oxidative stress, inflammation, HDL deficiency, or cardiovascular mortality in the end-stage renal disease populations. Similarly, high doses of antioxidant vitamins have failed to either ameliorate oxidative stress, inflammation, or improve overall mortality in end-stage renal disease. This article is intended to provide a brief review of the effects of CKD on HDL structure and function and pathways of lipid influx, efflux, synthesis, and catabolism in the artery wall and the diseased kidney.