Abstract: TH-PO0278
Depletion of Renal Cortical Collecting Duct-Secreted PCSK9 in Early Proteinuria Prevents Sustained Nephrotic Syndrome-Related Hypercholesterolemia
Session Information
- Glomerular Diseases: Cell Biology
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Zavala-Guevara, Itzel Pamela, Rush University Medical Center, Chicago, Illinois, United States
- Molina-Jijon, Eduardo, Rush University Medical Center, Chicago, Illinois, United States
- Gambut, Stephanie, Rush University Medical Center, Chicago, Illinois, United States
- Gomez-Sierra, Tania, Rush University Medical Center, Chicago, Illinois, United States
- Avila-Casado, Carmen, University Health Network, Toronto, Ontario, Canada
- Mace, Camille E., Rush University Medical Center, Chicago, Illinois, United States
- Clement, Lionel C., Rush University Medical Center, Chicago, Illinois, United States
Background
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol metabolism. We previously showed that the initiation of hypercholesterolemia in Nephrotic Syndrome (NS), in animal models of focal and segmental glomerulosclerosis and collapsing glomerulopathy, is related to PCSK9 secreted by the cortical collecting duct (CCD) in the kidney, whereas the established phase is due to PCSK9 secreted by the liver. In this study, we investigated if early neutralization of CCD-secreted PCSK9 could prevent sustained hypercholesterolemia in the established phase of Minimal Change Disease (MCD) associated with NS.
Methods
Sprague-Dawley male rats were injected with saline or puromycin aminonucleoside (PAN). To evaluate the therapeutic effect of PCSK9 depletion, rats were injected with anti-PCSK9 antibodies following PAN administration. Proteinuria, serum PCSK9, and serum total cholesterol and triglyceride levels were assessed. PCSK9 and SREBP2 gene and protein expression in the liver and kidney were studied by RealTime PCR, Western Blot and confocal microscopy. Human patient kidney biopsies were stained with PCSK9 and AQP2 antibodies to study PCSK9 protein expression and localization.
Results
After PAN treatment, rats developed significant proteinuria and serum PCSK9 levels increased on day 6, concomitantly with the development of hypercholesterolemia. In the kidney, a bimodal pattern of PCSK9 expression in the CCD was observed, increasing significantly on days 3, 6 and 7. As expected, the expression of the transcription factor SREBP2 was increased before PCSK9 on days 2 and 5. In the liver, SREBP2 and PCSK9 expression were unchanged or decreased, respectively. In human MCD, we found that PCSK9 expression is also increased in CCD. When we evaluated the therapeutic effect of anti-PCSK9 antibodies in the PAN rats, we found that although the animals develop proteinuria, they showed delayed and reduced hypercholesterolemia, with a transient increase in serum total cholesterol levels only on day 9 and significantly lower levels compared to the PAN group.
Conclusion
CCD-PCSK9 could become a new therapeutic target to prevent sustained hypercholesterolemia in NS patients in which prolonged hypercholesterolemia may worsen kidney disease and risk of cardiovascular disease.
Funding
- NIDDK Support