Abstract: FR-PO804
Differential Expression of Renal and Hepatic PCSK9 during Development of Hypercholesterolemia in the Passive Heymann Nephritis Rat Model of Nephrotic Syndrome
Session Information
- Glomerular Diseases: Inflammation and Immunology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Molina-Jijon, Eduardo, Rush University Medical Center, Chicago, Illinois, United States
- Mace, Camille E., Rush University Medical Center, Chicago, Illinois, United States
- Avila-Casado, Carmen, University of Toronto, Toronto, Ontario, Canada
- Clement, Lionel C., Rush University Medical Center, Chicago, Illinois, United States
Background
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of LDL-c levels in the liver. In the kidney, PCSK9 is expressed in the cortical collecting duct (CCD) where it plays a role of chaperone protein for the epithelial sodium channel. We showed increased PCSK9 expression in kidney biopsies of patients with primary glomerular disease and its implication in the initiation of development of hypercholesterolemia in the Buffalo-Mna rat (model of focal and segmental glomerulosclerosis) and the Rrm2b-/- mouse (model of collapsing glomerulopathy) (Molina-Jijon et al, 2020) following proteinuria. We then studied the expression of PCSK9 in the PHN rat (model of Membranous Nephropathy (MN)).
Methods
Male Sprague-Dawley rats were injected twice with sheep serum (Controls, 750 μl/rat on Day 0 and Day 1) or sheep anti-Fx1A antibody (PHN, 750 μl/rat on Day 0 and Day 1). Rats were euthanized on Days 3, 7, 10 and 17 after first injection. Proteinuria, PCSK9 and total cholesterol serum levels were assessed. PCSK9 gene and protein expression in liver and kidney were studied by Real Time PCR, Western blot, and confocal microscopy. Human patient kidney sections were stained with PCSK9 and AQP2 antibodies to study PCSK9 protein expression and localization.
Results
Control rats do not develop proteinuria neither hypercholesterolemia nor have high levels of serum PCSK9. PHN rats develop proteinuria from day 3 (4.26 ± 0.98 mg/18h, P<0.01; 198.73 ± 21.22 mg/18h at day 17, P<0.001), high serum PCSK9 levels from day 7 (60.427 ± 73.33 ng/ml, P<0.05; 1,404.96 ± 280.29 ng/ml at day 17, P<0.001), and hypercholesterolemia from day 7 (184.49 ± 7.98 mg/dL, P<0.001; 352.58 ± 29.16 mg/dL at day 17, P<0.001). PCSK9 protein and gene expression increased in the kidney but not in the liver at the same time points studied.
Conclusion
As PHN rats develop NS, PCSK9 protein level increases in the kidney, but not in the liver. CCD-PCSK9 may play a role in the initiation of hypercholesterolemia in MN-related NS. CCD-PCSK9 could become a new therapeutic target to prevent development of hypercholesterolemia in NS patients in which prolonged hypercholesterolemia may worsen kidney disease and increase risk of cardiovascular disease.
Funding
- NIDDK Support