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Kidney Week

Abstract: FR-PO148

Study of the Expression of Renal PCSK9 in the Rrm2b Mouse Model of Nephrotic Syndrome

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Molina-Jijon, Eduardo, Rush University Medical Center, Chicago, Illinois, United States
  • Gambut, Stephanie, Rush University Medical Center, Chicago, Illinois, United States
  • Mace, Camille E., Rush University Medical Center, Chicago, Illinois, United States
  • Avila-Casado, Carmen, University Health Network, University of Toronto, Toronto, Ontario, Canada
  • Clement, Lionel C., Rush University Medical Center, Chicago, Illinois, United States

Group or Team Name

  • Glomerular Disease Therapeutics Laboratory
Background

85% of American chronic disease patient presenting nephrotic syndrome (NS) have high levels of low density lipoprotein cholesterol (LDL-c), compared to only 31.5% in the American general population. A factor from the kidney might be responsible for the increased susceptibility for high levels of LDL-c in NS patients. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was shown to play an important role in the regulation of LDL-c levels in the liver. PCSK9 is expressed in the kidney at a lower level of expression compared to the liver, but its role in this organ is not clear. We decided to study the expression and the role of PCSK9 in NS in the Rrm2b mouse, a model collapsing glomerulopathy.

Methods

Male Rrm2b Control (+/+) and knock-out (-/-) mice (6 mice/group) were studied every week between the age 5 and 12 weeks. Albuminuria, PCSK9 and cholesterol serum levels were assessed. PCSK9 gene and protein expression in liver, kidney, intestine and serum were studied by RealTime PCR, Western blot, and confocal microscopy.

Results

Rrm2b+/+ mice do not develop albuminuria, hypercholesterolemia, or high levels of serum PCSK9. Compared to controls, Rrm2b-/- develop albuminuria from the age of 7 weeks (from 425±239 μg/18h at 7 weeks to 3895±381 at 10 weeks (P<0.001)). Serum PCSK9 levels significantly increase from the age of 8 weeks (from 19.75±5.21 ng/ml at 8 weeks (P<0.05) to 55.54±13.07 at 10 weeks (P<0.01)). Serum total cholesterol levels significantly increase from the age of 8 weeks (from 124.16±10.27 mg/dl at 8 weeks (P<0.05) to 567.58±72.96 at 10 weeks (P<0.001)). PCSK9 gene expression is relatively unchanged as animal age. PCSK9 protein expression was shown by Western blot to increase in the renal cortex from the age of 9 weeks, and decrease in the liver from the age of 7 weeks. By confocal microscopy, PCSK9 was shown to co-localize with Aquaporin-2, indicating expression in the collecting duct where its expression is increased from the age of 7 weeks.

Conclusion

As Rrm2b-/- mice age and develop NS, PCSK9 protein levels increase in the kidney and serum, and decrease in the liver. Collecting duct expressed PCSK9 may play an important role in the initiation of hypercholesterolemia in NS in the Rrm2b mouse model, as a link between the kidney and the liver.