Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate-PCSK9 Interaction

Pragyi Shrestha; Saritha Adepu; Romain R Vivès; Rana El Masri; Astrid Klooster; Fleur Kaptein; Wendy Dam; Stephan J L Bakker; Harry van Goor; Bart van de Sluis; Jacob van den Born

doi:10.1681/ASN.2020091376

Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate-PCSK9 Interaction

Pragyi Shrestha, Saritha Adepu, Romain R Vivès, Rana El Masri, Astrid Klooster, Fleur Kaptein, Wendy Dam, Stephan J L Bakker, Harry van Goor, Bart van de Sluis, Jacob van den Born^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

3 Citations (Scopus)

107 Downloads (Pure)

Abstract

Background Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol.

Methods Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Fromter (MWF) rats.

Results Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all P

Conclusions Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.

Original language	English
Pages (from-to)	1371-1388
Number of pages	18
Journal	Journal of the American Society of Nephrology
Volume	32
Issue number	6
DOIs	https://doi.org/10.1681/ASN.2020091376
Publication status	Published - Jun-2021

Keywords

CHRONIC KIDNEY-DISEASE
DENSITY-LIPOPROTEIN RECEPTOR
MOLECULAR-WEIGHT HEPARIN
SMOOTH-MUSCLE-CELLS
UP-REGULATION
PLASMA PCSK9
CARDIOVASCULAR-DISEASE
GENE-EXPRESSION
POOLED ANALYSIS
PROTEOGLYCANS

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10.1681/ASN.2020091376

Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate-PCSK9 InteractionFinal publisher's version, 13.7 MBLicence: Taverne

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Shrestha, P., Adepu, S., Vivès, R. R., Masri, R. E., Klooster, A., Kaptein, F., Dam, W., Bakker, S. J. L., van Goor, H., van de Sluis, B., & van den Born, J. (2021). Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate-PCSK9 Interaction. Journal of the American Society of Nephrology, 32(6), 1371-1388. https://doi.org/10.1681/ASN.2020091376

@article{15d2439446ff42f9a38ba2d5979294a6,

title = "Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate-PCSK9 Interaction",

abstract = "Background Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol.Methods Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Fromter (MWF) rats.Results Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all PConclusions Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.",

keywords = "CHRONIC KIDNEY-DISEASE, DENSITY-LIPOPROTEIN RECEPTOR, MOLECULAR-WEIGHT HEPARIN, SMOOTH-MUSCLE-CELLS, UP-REGULATION, PLASMA PCSK9, CARDIOVASCULAR-DISEASE, GENE-EXPRESSION, POOLED ANALYSIS, PROTEOGLYCANS",

author = "Pragyi Shrestha and Saritha Adepu and Viv{\`e}s, {Romain R} and Masri, {Rana El} and Astrid Klooster and Fleur Kaptein and Wendy Dam and Bakker, {Stephan J L} and {van Goor}, Harry and {van de Sluis}, Bart and {van den Born}, Jacob",

note = "Copyright {\textcopyright} 2021 by the American Society of Nephrology.",

year = "2021",

month = jun,

doi = "10.1681/ASN.2020091376",

language = "English",

volume = "32",

pages = "1371--1388",

journal = "Journal of the American Society of Nephrology",

issn = "1046-6673",

publisher = "AMER SOC NEPHROLOGY",

number = "6",

}

Shrestha, P, Adepu, S, Vivès, RR, Masri, RE, Klooster, A, Kaptein, F, Dam, W , Bakker, SJL , van Goor, H , van de Sluis, B & van den Born, J 2021, 'Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate-PCSK9 Interaction', Journal of the American Society of Nephrology, vol. 32, no. 6, pp. 1371-1388. https://doi.org/10.1681/ASN.2020091376

TY - JOUR

T1 - Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate-PCSK9 Interaction

AU - Shrestha, Pragyi

AU - Adepu, Saritha

AU - Vivès, Romain R

AU - Masri, Rana El

AU - Klooster, Astrid

AU - Kaptein, Fleur

AU - Dam, Wendy

AU - Bakker, Stephan J L

AU - van Goor, Harry

AU - van de Sluis, Bart

AU - van den Born, Jacob

PY - 2021/6

Y1 - 2021/6

N2 - Background Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol.Methods Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Fromter (MWF) rats.Results Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all PConclusions Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.

AB - Background Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol.Methods Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Fromter (MWF) rats.Results Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all PConclusions Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.

KW - CHRONIC KIDNEY-DISEASE

KW - DENSITY-LIPOPROTEIN RECEPTOR

KW - MOLECULAR-WEIGHT HEPARIN

KW - SMOOTH-MUSCLE-CELLS

KW - UP-REGULATION

KW - PLASMA PCSK9

KW - CARDIOVASCULAR-DISEASE

KW - GENE-EXPRESSION

KW - POOLED ANALYSIS

KW - PROTEOGLYCANS

U2 - 10.1681/ASN.2020091376

DO - 10.1681/ASN.2020091376

M3 - Article

C2 - 33758009

SN - 1046-6673

VL - 32

SP - 1371

EP - 1388

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

IS - 6

ER -