Role Of PCSK9 In Hyperlipemia Of Nephrotic Syndrome And The Effect Of Lovastatin Intervention

Background:Primary nephrotic syndrome leads to elevation of serum total and LDL cholesterol,and hypertriglyceridemia is common.This is mainly due to limitation of LDL clearance,which is caused by hepatic LDL receptor(LDLR)deficiency.There are less data to clarify the mechanism(s)by which NS causes LDLR deficiency.In hyperlipidemia,it was found that PCSK9 mediated LDLR degradation through post-transcription pathway,and there was a correlation between the expression of PCSK9 and HMG-Co A(a key enzyme to regulate cholesterol metabolism),both of which were regulated by the sterol-regulatory element-binding protein 2(SREBP2)Elevation or lowering of free cholesterol in hepatocytes could down-regulate or raise the expression of SREBP2.Therefore we aimed to explore the role of PCSK9 in hyperlipemia of nephrotic syndrome and lovastatin intervention.Methods:18 male SD rats were randomly divided into three groups:control group,nephropathic group and statin treatment group.Nephrotic syndrome was created with single intravenous injection adriamycin(7mg/kg).After two weeks,statin treatment group was given by intragastric administration with lovastain(20mg/kg,qd×2w)and other groups was given with same Carboxymethyl cellulose sodium(CMC).Before rats were sacrificed,we measured levels of 24 h urine protein,renal function?albumin and lipid levels.We observed renal pathological forms through HE and PAS staining and the expression of LDLR and PCSK9 in liver tissues were detected with Q-PCR and Western-Blot analysis.Results:The expression of LDLR m RNA did not reach statistical difference among three groups.The two groups presented a significant elevation in hepatic PCSK9 m RNA and protein expression than in control group.Additonally,there was a marked upregulation of PCSK9 in statin treatment group compared with NS group.Levels of serum total cholesterol and LDL-c showed a strong linear relationship with the expression of PCSK9 m RNA in NS group(P<0.05),and in statin treatment group this relationship did not exsit.Conclusions: Hyperlipidemia in NS is associated with upregulation of PCSK9,and statin treatment can further increase the expression of PCSK9.