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Abstract: TH-PO1083

Role of Renal PCSK9 in the Rrm2b Mouse Model of Nephrotic Syndrome

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

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
Background

85% of US chronic disease patient presenting nephrotic syndrome (NS) have high levels of low density lipoprotein cholesterol (LDL-c), compared to 31.5% in the general population. 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 collecting duct (CD) where it plays a role of chaperon protein for the epithelial sodium channel (ENaC). We studied the expression of PCSK9 in NS in the Rrm2b-/- mouse, a model of collapsing glomerulopathy.

Methods

(1) Rrm2b Control (+/+) and knock-out (-/-) mice were followed weekly 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. (2) 8 week-old mice were treated or not with amiloride, a specific inhibitor of ENaC located in the renal CD.

Results

Rrm2b+/+ mice do not develop albuminuria, hypercholesterolemia, or high levels of serum PCSK9. Rrm2b-/- develop albuminuria from the age of 7 weeks (425±239 μg/18h, P<0.001) and serum PCSK9 and total cholesterol levels significantly increase from the age of 8 weeks (19.75±5.21 ng/ml, P<0.05, and 124.16±10.27 mg/dl, P<0.05, respectively). 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 CD where its expression is increased from the age of 7 weeks.
When treated with amiloride, Rrm2b-/- mice show elevated levels of blood PCSK9 and cholesterol compared to mice without treatment. Amiloride blocks ENaC, the CD cells then increase the number of active ENaC present in the plasma membrane and the secretion of PCSK9, initiating hypercholesterolemia.

Conclusion

As Rrm2b-/- mice age and develop NS, PCSK9 protein levels increase in the kidney and serum, and decrease in the liver. Amiloride treatment showed that PCSK9 secreted by CD cells into the circulation induces earlier and higher hypercholesterolemia. CD expressed PCSK9 may play an important role in hypercholesterolemia in NS in the Rrm2b mouse model, as a link between the kidney and the liver.

Funding

  • NIDDK Support