Down-regulation of VLDL receptor expression in chronic experimental renal failure

Abstract

VLDL receptor (VLDL-R) is a novel member of the LDL receptor gene family with distinct tissue distribution and function. It binds and internalizes VLDL particles and is primarily expressed in skeletal muscle, heart, brain and adipose tissue, which use fatty acids for energy production or storage. CRF is associated with elevated serum triglyceride and VLDL concentrations and depressed VLDL and chylomicron clearance. We have recently shown marked down-regulation of lipoprotein lipase expression in CRF. This study was conducted to test the hypothesis that VLDL-R expression may be similarly depressed in CRF. To this end, VLDL-R mRNA (Northern blot) and protein mass (Western blot) of skeletal muscle (soleus) and heart were measured in male Sprague-Dawley rats six weeks after 5/6 nephrectomy (CRF group) or sham operation (NL group). A group of erythropoietin (EPO)-treated (150 U/kg twice weekly) CRF animals was included to determine the possible effect of EPO-deficiency anemia (EPO-CRF group). Subgroups of animals were studied at weeks 1, 3 and 6. The CRF group showed a fivefold increase in plasma triglyceride concentration. This was associated with an impressive fourfold reduction in heart and skeletal muscle VLDL-R mRNA and protein mass. VLDL-R mRNA levels in the heart and skeletal muscle were directly related to creatinine clearance and inversely related to serum triglyceride and VLDL concentrations. EPO therapy led to a mild improvement in CRF hypertriglyceridemia but failed to improve VLDL-R expression. Thus, the rise in plasma triglyceride and VLDL concentrations in CRF animals was associated with marked down-regulation of VLDL-R expression. Down-regulation of VLDL-R expression, shown here for the first time, reveals another facet of disturbed lipid metabolism in CRF.