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Abstract: SA-PO955

Differential Expression of Renal and Hepatic PCSK9 During Development of Hypercholesterolemia in the Puromycin Aminonucleoside Nephrosis Rat Model of Nephrotic Syndrome

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Molina-Jijon, Eduardo, 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, Toronto, Ontario, Canada
  • Clement, Lionel C., Rush University Medical Center, Chicago, Illinois, United States
Background

In the US, 85% of patients with nephrotic syndrome (NS) have hypercholesterolemia, compared to 31.5% of the general population. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a main role in the regulation of LDL-cholesterol in the liver. In the kidney, PCSK9 is expressed in the cortical collecting duct (CCD) where acts as a chaperone for the epithelial sodium channel. We showed that PCSK9 is increased in kidney biopsies of patients with NS and that it is implicated in the initiation of hypercholesterolemia in two animal models, Buffalo-Mna rats (model of focal and segmental glomerulosclerosis) and Rrm2b-/- mice (model of collapsing glomerulopathy) (Molina-Jijon et al, 2020). In this study, we investigate the expression of PCSK9 in puromycin aminonucleoside (PAN) nephrosis in rats, a model of human Minimal Change Disease (MCD)

Methods

Sprague-Dawley rats were injected with saline 0.9% (control) or PAN (15 mg/100 g). Rats were euthanized daily from day 1 to 7 after PAN injection. Proteinuria, PCSK9 and serum cholesterol were assessed. PCSK9 gene and protein expression in liver and kidney were studied by RealTime PCR and Western blot

Results

Control rats did not develop proteinuria, hypercholesterolemia or high serum PCSK9. PAN rats developed proteinuria (mg/18h) from day 4 after injection (0.82±0.1 day 0; 4.4± 1 day 4; 63±17 day 5; 145±7 day 6 and 128±13 day 7). Serum PCSK9 (ng/mL) significantly increased from day 5 (144±26 day 0; 404±81 day 5; 1635±263 day 6; 1816 ± 191 day 7), and hypercholesterolemia (mg/dL) significantly developed from day 6 to 7 (93±6 day 0; 326.80±37 day 6; 352±10 day 7). In the kidney, PCSK9 expression increased from day 3 after injection, and was not modified in the liver. Similarly, PCSK9 mRNA increased in the kidney from day 5 with no significant modification in the liver (fold change mRNA expression=18.9 for renal cortex vs 2.4 for liver day 5; 11.4 vs 2.6 day 6; 20.5 vs 1.6 day 7)

Conclusion

As rats develop NS, PCSK9 protein level increase in the kidney and serum and did not change in the liver. PCSK9 from CCD may play a role in the initiation of hypercholesterolemia in MCD-related nephrotic syndrome and could become a new therapeutic target to prevent development of hypercholesterolemia in nephrotic syndrome patients

Funding

  • NIDDK Support