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Background: A high level of circulating PCSK9 binds to the LDL receptor, reduces its cell's surface density and leads to hypercholesterolemia. The aim of this study was to examine the circulating PCSK9 level in patients with kidney disease. Methods: Out of the patients treated in our Departments we selected: (a) 44 patients with CKD stage 3 and 4 (b) 29 patients with CKD stage 5 on maintenance hemodialysis treatment; and (c) 20 patients after successful renal transplantation. Thirty-four subjects, without CKD formed the control group. Serum biochemical parameters' concentrations were assayed by a certified laboratory. Serum PCSK9 concentration was estimated by a commercially available ELISA kit. Results: The mean serum concentration of PCSK9 in patients with kidney disease was higher than in the control group (238.7 ± 64.5 vs. 536.7 ± 190.4; p < 0.001). A strong negative correlation between serum PCSK9 concentration and eGFR was found (r = -0.66; p < 0.001), as well as between serum concentrations of PCSK9 and total- (r = 0.482; p < 0.05) or LDL-cholesterol (r = 0.533; p < 0.05), but exclusively in patients not receiving statins. The elevated serum concentration of PCSK9 in patients before hemodialysis session declined afterwards, reaching the values observed in patients after kidney transplantation and in the control group. Conclusion: The circulating PCSK9 concentration is increased in patients with CKD; however, this is not accompanied by hypercholesterolemia. The positive correlations between PCSK9/TCh and PCSK9/LDL-Ch have been found only in patients not treated with statins. The elevated circulating PCSK9 level is corrected by maintenance hemodialysis treatment and normalized by a successful kidney transplantation.

Chemerin is an adipokine modulating inflammatory response and affecting glucose and lipid metabolism. These disturbances are common in CKD. The aim of the study was: (a) to evaluate circulating chemerin level at different stages of CKD; (b) to measure subcutaneous adipose tissue chemerin gene expression; (c) to estimate the efficiency of renal replacement therapy in serum chemerin removal. 187 patients were included into the study: a) 58 patients with CKD; (b) 29 patients on hemodialysis; (c) 20 patients after kidney transplantation. 80 subjects constituted control group. Serum chemerin concentration was estimated by ELISA. The adipose tissue chemerin mRNA level was measured by RT-qPCR. The mean serum chemerin concentration in CKD patients was 70% higher than in the control group (122.9 ± 33.7 vs. 72.6 ± 20.7 ng/mL; p < 0.001) and it negatively correlated with eGFR (r = -0.71, p < 0.001). The equally high plasma chemerin level was found in HD patients and a HD session decreased it markedly (115.7 ± 17.6 vs. 101.5 ± 16.4 ng/mL; p < 0.001). Only successful kidney transplantation allowed it to get down to the values noted in controls (74.8 ± 16.0 vs. 72.6 ± 20.7 ng/mL; n.s.). The level of subcutaneous adipose tissue chemerin mRNA in CKD patients was not different than in patients of the control group. The study demonstrates that elevated serum chemerin concentration in CKD patients: (a) is related to kidney function, but not to increased chemerin production by subcutaneous adipose tissue, and (b) it can be efficiently corrected by hemodialysis treatment and normalized by kidney transplantation.

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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.

Inflammation related to chronic kidney disease (CKD) is an important clinical problem. We recently determined that hepatocyte nuclear factor 1α (HNF1α) was upregulated in the livers of chronic renal failure (CRF) rats—experimental model of CKD. Considering that the promoter region of gene encoding C-reactive protein (CRP) contains binding sites for HNF1α and that the loss-of-function mutation in the Hnfs1α leads to significant reduction in circulating CRP levels, we hypothesized that HNF1α can activate the Crp in CRF rats. Here, we found coordinated upregulation of genes encoding CRP, interleukin-6 (IL-6), HNF1α, and HNF4α in the livers and white adipose tissue (WAT) of CRF rats, as compared to the pair-fed and control animals. This was accompanied by elevated serum levels of CRP and IL-6. CRP and HNFs’ mRNA levels correlated positively with CRP and HNFs’ protein levels in the liver and WAT. Similar upregulation of the Crp, Il-6, and Hnfs in the liver and WAT and increased serum CRP and IL-6 concentrations were found in lipopolysaccharide (LPS)-induced systemic inflammation in rats. Moreover, silencing HNF1α in HepG2 cells by small interfering RNA led to decrease in CRP mRNA levels. Our results suggests that (a) HNFs act in concert with IL-6 in the upregulation of CRP production by the liver and WAT, leading to an increase in circulating CRP concentration in CRF rats and (b) CRF-related inflammation plays an important role in the upregulation of genes that encode HNFs and CRP in the liver and WAT of CRF rats.Electronic supplementary materialThe online version of this article (10.1007/s11010-018-3268-1) contains supplementary material, which is available to authorized users.