Up-regulation of liver Pcsk9 gene expression as a possible cause of hypercholesterolemia in experimental chronic renal failure.
Dyslipidemia commonly present in patients with chronic kidney disease (CKD) has been recently linked to increased proprotein convertase subtilisin/kexin type 9 (PCSK9) serum concentration. We tested a hypothesis that increased liver PCSK9 biosynthesis could be partially responsible for the elevated circulating PCSK9 level, and subsequently contribute to hypercholesterolemia observed in subjects with CKD. Rat model of chronic renal failure (CRF) was used in the study. Animals underwent a 5/6 nephrectomy or a sham operation. Liver expression of Pcsk9, sterol regulatory element-binding transcription factor 2 (Srebf-2), and β-actin were quantified by real-time RT-PCR. Liver protein levels of PCSK9, LDL-receptor (LDL-R), and SREBF-2 were analyzed using Western blotting. Serum PCSK9 concentration was estimated by immunoassay. Rats with an experimental CRF as compared to pair-fed and control ones were characterized by: (a) an up-regulation of liver Pcsk9 and Srebf-2 genes expression with parallel increase of serum PCSK9 concentration; (b) a decrease in liver LDL-R protein level, and (c) an increase of serum total and LDL-cholesterol concentrations. We also found significant correlations between serum creatinine and liver PCSK9 mRNA levels (r = 0.88, p < 0.001) and between serum creatinine and circulating PCSK9 levels (r = 0.73, p < 0.001). The results suggest that a rat model of CRF is associated with an increased liver Pcsk9 gene expression. The coordinated up-regulation of Pcsk9 and Srebf-2 genes expression suggests that SREBF-2 may play a key role in regulation of Pcsk9 gene expression, circulating PCSK9 level, and hypercholesterolemia in experimental CRF.
Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, ul. Debinki 7, 80-211, Gdańsk, Poland.
Elzbieta
E
Sucajtys-Szulc
Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, ul. Debinki 7, 80-211, Gdańsk, Poland.
Marek
M
Szolkiewicz
Department of Biochemistry, Medical University of Gdansk, ul. Debinki 1, 80-211, Gdańsk, Poland.
Julian
J
Swierczynski
Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, ul. Debinki 7, 80-211, Gdańsk, Poland. bolo@gumed.edu.pl.
Boleslaw
B
Rutkowski
D000818:Animals; D006937:Hypercholesterolemia / Q000235:genetics*; D008099:Liver / Q000201:enzymology*; D008297:Male; D000071449:Proprotein Convertase 9; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D015854:Up-Regulation
D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; C510804:PCSK9 protein, rat; D000071449:Proprotein Convertase 9; D012697:Serine Endopeptidases
CRF; Hypercholesterolemia; LDL; LDL-R; PCSK9; SREBF-2