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Abstract: TH-OR20

PCSK9 Targets Megalin in the Kidney Proximal Tubule and Aggravates Proteinuria in Nephrotic Syndrome

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Hummelgaard, Sandra, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Skeby, Cecilie Kirkeby, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Gustafsen, Camilla, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Petrillo, Federica, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Frederiksen, Kathrine Pii, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Olsen, Ditte, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Kristensen, Tilde, Aarhus Universitetshospital, Aarhus, Denmark
  • Ivarsen, Per Ramlov, Aarhus Universitetshospital, Aarhus, Denmark
  • Madsen, Peder, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Christensen, Erik I., Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Nielsen, Rikke, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Birn, Henrik, Aarhus Universitetshospital, Aarhus, Denmark
  • Glerup, Simon, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Weyer, Kathrin, Aarhus Universitet, Aarhus, Midtjylland, Denmark

Proteinuria is a prominent feature of chronic kidney disease (CKD). Interventions that reduce proteinuria slow CKD progression and the associated risk of cardiovascular disease (CVD). We here propose a mechanistic coupling between proteinuria and the CVD-risk protein PCSK9 involving the receptor megalin.


Urinary PCSK9 excretion was determined in megalin knockout (KO) mice and patients carrying megalin pathogenic variants as well as minimal change disease patients at baseline and remission after standard prednisolone treatment (1 mg/kg/day). Mechanistical studies were performed in proximal tubular cell cultures (LLC-PK1 cells). PCSK9-mediated megalin regulation and proteinuria were investigated in PCSK9 KO mice, PCSK9 overexpressing mice as well as wildtype and nephrotic podocin KO mice treated with the PCSK9 inhibitor alirocumab (30 mg/kg/day and 50 mg/kg/day, respectively). Kidney injury was evaluated in podocin KO mice treated with alirocumab for 14 days.


We find that 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 are characterized by elevated urinary PCSK9 excretion. Interestingly, PCSK9 knockout mice displayed increased renal 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 is potentially accelerated under disease conditions as genetic destruction of the glomerular filtration barrier in mice, and minimal change nephropathy in humans, resulted in markedly increased tubular PCSK9 uptake and urinary PCSK9 excretion. Pharmacological PCSK9 inhibition increased renal megalin, while reducing urinary albumin excretion and kidney injury markers in nephrotic mice.


In conclusion, glomerular damage increases filtration of PCSK9 and concomitantly megalin degradation, resulting in escalated proteinuria. Targeting PCSK9 may be beneficial to attenuate proteinuria-induced kidney injury in CKD.


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