Up-regulation of liver Pcsk9 gene expression as a possible cause of hypercholesterolemia in experimental chronic renal failure.

Elzbieta Sucajtys-Szulc,Boleslaw Rutkowski,Julian Swierczynski,Marek Szolkiewicz

doi:10.1007/s11010-015-2590-0

Abstract

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.

Highlights

Dyslipidemia, one of the most potent cardiovascular risk factor in patients with chronic kidney disease (CKD), significantly contributes to increased morbidity and mortality in this group of patients as compared to general population [1]
We postulated that proprotein convertase subtilisin/kexin type 9 (PCSK9) overproduction could partially contribute to its elevated serum concentration found in patients with CKD [20]
To gain a better insight into the role of PCSK9 in a development of chronic renal failure (CRF)-related hypercholesterolemia, we examined liver Pcsk9 gene expression in rat model of this disease

Summary

Introduction

Dyslipidemia, one of the most potent cardiovascular risk factor in patients with chronic kidney disease (CKD), significantly contributes to increased morbidity and mortality in this group of patients as compared to general population [1]. Lipid abnormalities themselves accelerate progression of CKD [2]. An evaluation of the molecular mechanism leading to CKD-related lipid disturbances is necessary for a better understanding and treatment of the disease. In our in vivo experimental model, cholesterol biosynthesis rate was increased only twofold, while circulating cholesterol concentration was 3–4-times higher in CRF rats when compared to control [5]. One can assume that the increased cholesterol biosynthesis is not the only process contributing to hypercholesterolemia in experimental CRF rats

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