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

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Visual Abstract

Significance Statement

Hypertension and elevated levels of LDL cholesterol (LDLc) are vital risk factors for cardiovascular disease (CVD) in patients with CKD. Although statins indisputably reduce plasma cholesterol levels, not all patients with renal disease benefit from them, making CVD the leading cause of CKD-related mortality. CKD induces hyperelongation of hepatic heparan sulfate (HS) chains from HS proteoglycans (HSPG), thereby increasing the HSPG–proprotein convertase subtilisin kexin type-9 (PCSK9) interaction. These changes associate with elevated LDLc levels, without affecting LDL-receptor expression. This study, using rat models, discloses a novel mechanism behind hypercholesterolemia in CKD with prospects for future investigation of the HSPG-PCSK9 interaction and development of novel heparin-related glycomimetics targeting interruption of HSPG-PCSK9 binding.

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-Frömter (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<0.05), which were most apparent in hypertensive MWF-CKD rats. Hepatic PCSK9 expression increased in both CKD groups (P<0.05), with unusual sinusoidal localization, which was not seen in 22-week-old rats. Heparan sulfate (HS) disaccharide analysis, staining with anti-HS mAbs, and mRNA expression of HS polymerase exostosin-1 (Ext-1), revealed elongated HS chains in both CKD groups. Solid-phase competition assays showed that the PCSK9 interaction with heparin-albumin (HS-proteoglycan analogue) was critically dependent on polysaccharide chain length. VLDL binding to HS from CKD livers was reduced (P<0.05). Proteinuria and plasma creatinine strongly associated with plasma cholesterol, PCSK9, and HS changes.

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.

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