Proprotein convertase subtilisin/kexin type 9 targets megalin in the kidney proximal tubule and aggravates proteinuria in nephrotic syndrome.

Abstract

Proteinuria is a prominent feature of chronic kidney disease. Interventions that reduce proteinuria slow the progression of chronic kidney disease and the associated risk of cardiovascular disease. Here, we propose a mechanistic coupling between proteinuria and proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of cholesterol and a therapeutic target in cardiovascular disease. PCSK9 undergoes glomerular filtration and is captured by megalin, the receptor responsible for driving protein reabsorption in the proximal tubule. Accordingly, megalin-deficient mice and patients carrying megalin pathogenic variants (Donnai Barrow syndrome) were characterized by elevated urinary PCSK9 excretion. Interestingly, PCSK9 knockout mice displayed increased kidney megalin while PCSK9 overexpression resulted in its reduction. Furthermore, PCSK9 promoted trafficking of megalin to lysosomes in cultured proximal tubule cells, suggesting that PCSK9 is a negative regulator of megalin. This effect can be accelerated under disease conditions since either genetic destruction of the glomerular filtration barrier in podocin knockout mice or minimal change disease (a common cause of nephrotic syndrome) in patients resulted in enhanced tubular PCSK9 uptake and urinary PCSK9 excretion. Pharmacological PCSK9 inhibition increased kidney megalin while reducing urinary albumin excretion in nephrotic mice. Thus, glomerular damage increases filtration of PCSK9 and concomitantly megalin degradation, resulting in escalated proteinuria.

• Authors: Cecilie K Skeby, Sandra Hummelgaard, Camilla Gustafsen, Federica Petrillo, Kathrine P Frederiksen, Ditte Olsen, Tilde Kristensen, Per Ivarsen, Peder Madsen, Erik I Christensen, Rikke Nielsen, Henrik Birn, Simon Glerup, Kathrin Weyer
• Journal: Kidney international (Kidney Int) Vol. 104 Issue 4 Pg. 754-768 (10 2023) ISSN: 1523-1755 [Electronic] United States
• PMID: 37406929 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• PCSK9 protein, human
• Proprotein Convertase 9
• Low Density Lipoprotein Receptor-Related Protein-2
• Subtilisins

Topics

• Humans
• Mice
• Animals
• Nephrotic Syndrome (pathology)
• Proprotein Convertase 9 (metabolism)
• Low Density Lipoprotein Receptor-Related Protein-2
• Cardiovascular Diseases (metabolism)
• Proteinuria (genetics)
• Kidney Tubules, Proximal (pathology)
• Renal Insufficiency, Chronic (pathology)
• Mice, Knockout
• Subtilisins (metabolism)