Nephrotic syndrome causes upregulation of HDL endocytic receptor and PDZK-1-dependent downregulation of HDL docking receptor

Abstract

Background. Nephrotic syndrome (NS) is associated with dysregulation of lipid/lipoprotein metabolism and impaired high-density lipoprotein (HDL)-mediated reverse cholesterol transport and atherosclerosis.HDLserves as vehicle for transport of surplus lipids from the peripheral tissues for disposal in the liver via two receptors: (i) scavenger receptor class B type I (SR-BI) which serves as a docking receptor, enabling HDL to unload its lipid cargo and return to circulation to repeat the cycle, and (ii) beta chain ATP synthase which serves as the endocytic receptor mediating removal and catabolism of lipid-poorHDL. SR-BI abundance is regulated by PDZ-containing kidney protein 1 (PDZK1), a multifunctional protein, which prevents SRB-1 degradation at the post-translational level. This study explored the effect of NS on hepatic expression of these important molecules. Methods. Gene expression, protein abundance and immunohistological appearance of the above proteins were measured in the liver of rats with puromycin-induced NS and control rats. Results. The nephrotic animals exhibited severe proteinuria, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, reduced HDL/total cholesterol ratio, normal glomerular filtration rate, significant upregulation of the endocytic HDL receptor messenger RNA (mRNA) and protein (P < 0.005) and significant reduction of SR-BI protein (P < 0.002) despite its normal mRNA abundance. The reduction in SR-BI protein abundance in NS animals was accompanied by parallel reductions in PDZK1 mRNA (P ¼ 0.02) and protein abundance (P ¼ 0.012). Conclusions. NS results in elevation of hepatic HDL endocytic receptor and deficiency of HDL docking receptor. The latter is associated with and, in part, mediated by downregulation of PDZK1. Together, these abnormalities can increase catabolism and diminish recycling of HDL and contribute to the defective reverse cholesterol/lipid transport in NS. Keywords: atherosclerosis; cardiovascular disease; dyslipidemia; proteinuria; reverse cholesterol transport