Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure

BACKGROUND: Chronic renal failure (CRF) is associated with an atherogeniclipid profile and an increased risk of ischaemic cardiovascular disease.The associated hyperlipidaemia is reportedly ameliorated by erythropoietin(Epo) therapy. According to a recent report, rats studied 3 weeks after 5/6nephrectomy and fed a high- protein diet exhibited increased activities ofhepatic HMG-CoA reductase (HMG-CoAR) and cholesterol 7 alpha-hydroxylase(Ch-7 alpha- H), despite normal corresponding mRNA values. DESIGN ANDMETHODS: This study was designed to examine the effects of naturallyprogressing CRF of longer duration as well as those of Epo therapy on geneexpressions of the key factors involved in hepatic cholesterol metabolism,i.e., LDL receptor (LDLR), HMG-CoAR, and Ch-7 alpha-H. Sprague-Dawley ratswere randomized to the CRF group (5/6 nephrectomy), Epo-treated CRF group(given Epo 150 U/kg/twice weekly) and sham-operated, placebo- treatednormal controls. They were allowed free access to regular rat chow andstudied 6 weeks after surgery. Liver mRNAs and protein mass or activitiesof the above factors were studied. RESULTS: Plasma cholesterolconcentration was significantly increased in the CRF group (P < 0.001)and was modestly lowered (P < 0.05) by Epo therapy. However, microsomalcholesterol concentration and LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA as wellas HMG-CoAR activity, and Ch-7 alpha-H and LDLR protein mass measurementswere virtually identical in the three groups. Thus, hepatic LDLR, HMG-CoAR,and Ch-7 alpha-H mRNA and protein measurements in rats with CRF weresimilar to those of the normal control group representing an inappropriateresponse to the associated hypercholesterolemia. Epo therapy led to partialamelioration of CRF- associated hypercholesterolaemia with no discernibleeffect on hepatic tissue expression of the above factors.