Abstract: SA-PO838
Dyslipidemia in Nephrotic Rats Associates with Increased Hepatic PCSK9 – Heparan Sulfate Interaction
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Shrestha, Pragyi, University of Groningen, Groningen, Netherlands
- Van de sluis, Bart, UMC Groningen, Groningen, Groningen, Netherlands
- van den Born, Jacob, Univ. Med. Center Groningen, Groningen, Netherlands
Background
Dyslipidemia characterized by higher levels of plasma lipids (triglyceride and cholesterol) increases the risk for cardiovascular disease in patients with Chronic Kidney Diseases (CKD). Here, our aim is to investigate the role of the LDL receptor (LDLR), heparan sulfate (HS) side chains of syndecan-1 and Proprotein convertase subtilisin/kexin type 9 (PCSK9) in CKD-related dyslipidemia using a dyslipidemic proteinuric rat model.
Methods
Eight male Wistar rats received 1.8 mg adriamycin/kg BW i.v. to induce proteinuria (ADR). Six control rats were injected with saline. Kidney function, proteinuria, and serum lipids were monitored weekly. Animals were sacrificed after 12 weeks. Tissues and plasma were collected. Expression of LDLR, syndecan-1, HS and PCSK9 were evaluated in the liver by immunofluorescence staining (IF), western blotting (WB) and qRT-PCR. Plasma PCSK9 was measured by ELISA. Mann Whitney test and Spearman Rank correlation were used for statistics.
Results
ADR showed increased proteinuria and serum lipids (all p<0.001) compared to controls without differences in protein and mRNA expression of LDLR. Interestingly, the localization of PCSK9 to the liver sinusoids was however significantly increased in ADR compared to controls (p<0.001, IF), without changes in gene expression. Serum triglyceride and cholesterol correlated with serum PCSK9 (r=0.59, p=0.0035; r=0.71, p=0.006) and with liver PCSK9 (r=0.83, p=0.0004; r=0.80, p=0.001 respectively). Moreover, PCSK9 protein was found to interact strongly with HS, and interaction was highly dependent on HS sulfation and chain length. Disaccharide profiling of HS revealed a remarkable increase in 6-O-sulfation of liver HS, which could be due to lower hepatic Sulf2 mRNA expression (p=0.06). Inverse association was found between serum triglyceride and cholesterol with Sulf2 mRNA levels (r=-0.67, p=0.01; r=-0.64, p=0.02).
Conclusion
Dyslipidemia in nephrotic rats is related to increased interaction of PCSK9 with hepatic syndecan-1/HS, which might hamper TRL clearance capacity.
Funding
- Government Support - Non-U.S.