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

Pragyi Shrestha1, Saritha Adepu1, Romain R Vivès2

  • 1Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Journal of the American Society of Nephrology : JASN
|March 24, 2021
PubMed

Insights

Chronic kidney disease (CKD) alters liver function, increasing proprotein convertase subtilisin/kexin type 9 (PCSK9) and heparan sulfate (HS) chain length. This leads to dyslipidemia in CKD patients.

Area of Science:

  • Nephrology
  • Cardiovascular Science
  • Biochemistry

Background:

  • Dyslipidemia is a significant risk factor for chronic kidney disease (CKD).
  • The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs).
  • HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9), and renal failure impacts hepatic lipoprotein metabolism.

Purpose of the Study:

  • To investigate the impact of CKD on hepatic lipoprotein metabolism and PCSK9 activity in rats.
  • To explore the role of heparan sulfate (HS) chain length in PCSK9-lipoprotein interactions in CKD.

Main Methods:

  • CKD was induced in Wistar and Munich-Wistar-Frömter (MWF) rats via uninephrectomy and aging.
  • Evaluated proteinuria, plasma creatinine, and hypercholesterolemia.
  • Assessed hepatic PCSK9 expression, HS chain length, and VLDL binding to hepatic HS.

Main Results:

  • CKD rats exhibited proteinuria, elevated plasma creatinine, and hypercholesterolemia, particularly in hypertensive MWF-CKD rats.
  • Hepatic PCSK9 expression increased in CKD rats with unusual sinusoidal localization.
  • CKD livers showed elongated HS chains, reduced VLDL binding to HS, and a strong correlation between proteinuria, creatinine, and PCSK9/HS changes.

Conclusions:

  • Progressive CKD induces hepatic HS elongation, increasing PCSK9 interaction.
  • This interaction may impair hepatic lipoprotein uptake, contributing to dyslipidemia in CKD.
  • PCSK9 and HS represent potential therapeutic targets for managing dyslipidemia in CKD.
Abstract

Keywords:
PCSK9chronic kidney diseasedyslipidemiaheparan sulfatesyndecan-1

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