Upregulation of hepatic LDL receptor-related protein in nephrotic syndrome: response to statin therapy.
Nephrotic syndrome (N-S) is associated with elevated plasma concentration and impaired clearance of VLDL, chylomicrons (CM), and their atherogenic remnants. These abnormalities are largely due to lipoprotein lipase, hepatic triglyceride lipase, and VLDL receptor deficiencies and impaired HDL-mediated shuttling of apoE and apoC between the nascent and remnant VLDL and CM. LRP is a multifaceted endocytic receptor that is heavily expressed in the liver. LRP recognizes at least 30 different ligands including VLDL and CM remnants. These observations prompted the present study to discern the effect of N-S on hepatic LRP gene and protein expressions. The study further sought to explore the effect of lipid-lowering therapy on LRP expression in N-S. Sprague-Dawley rats were randomized to the N-S (given ip injections of puromycin aminonucleoside; 130 mg/kg on day 1, 60 mg/kg on day 14) and placebo-injected control groups. On day 14, animals were subdivided into statin-treated (rosuvastatin; 20 mg x kg(-1) x day(-1) mixed with powdered chow) and untreated groups and studied on day 28. The untreated N-S group exhibited severe proteinuria, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and marked elevation of hepatic tissue LRP mRNA and protein abundance. Statin administration for 2 wk resulted in significant improvements of plasma lipid profile, proteinuria, and hypoalbuminemia as well as hepatic LRP mRNA and protein abundance. In contrast, statin administration had no significant effect on either plasma lipids or hepatic LRP levels in the normal control rats. In conclusion, N-S results in marked upregulation of hepatic LRP expression that is partly reversed with statin administration. These findings exclude depressed hepatic LRP expression as the primary cause of elevated plasma lipoprotein remnants in N-S.
Kim
Sara
S
Division of Nephrology and Hypertension, University of California, Irvine, California, USA.
Kim
Choong H
CH
Vaziri
Nosratola D
ND
D000818:Animals; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D005464:Fluorobenzenes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D026563:LDL-Receptor Related Protein-Associated Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D026563:LDL-Receptor Related Protein-Associated Protein; D011743:Pyrimidines; D013449:Sulfonamides; D014280:Triglycerides; D012313:RNA; D000068718:Rosuvastatin Calcium; D002784:Cholesterol