Differential Expression of Renal and Hepatic PCSK9 during Development of Hypercholesterolemia in the Passive Heymann Nephritis Rat Model of Nephrotic Syndrome
Bibliographic record
Abstract
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of LDL-c levels in the liver. In the kidney, PCSK9 is expressed in the cortical collecting duct (CCD) where it plays a role of chaperone protein for the epithelial sodium channel. We showed increased PCSK9 expression in kidney biopsies of patients with primary glomerular disease and its implication in the initiation of development of hypercholesterolemia in the Buffalo-Mna rat (model of focal and segmental glomerulosclerosis) and the Rrm2b-/- mouse (model of collapsing glomerulopathy) (Molina-Jijon et al, 2020) following proteinuria. We then studied the expression of PCSK9 in the PHN rat (model of Membranous Nephropathy (MN)). Methods: Male Sprague-Dawley rats were injected twice with sheep serum (Controls, 750 μl/rat on Day 0 and Day 1) or sheep anti-Fx1A antibody (PHN, 750 μl/rat on Day 0 and Day 1). Rats were euthanized on Days 3, 7, 10 and 17 after first injection. Proteinuria, PCSK9 and total cholesterol serum levels were assessed. PCSK9 gene and protein expression in liver and kidney were studied by Real Time PCR, Western blot, and confocal microscopy. Human patient kidney sections were stained with PCSK9 and AQP2 antibodies to study PCSK9 protein expression and localization. Results: Control rats do not develop proteinuria neither hypercholesterolemia nor have high levels of serum PCSK9. PHN rats develop proteinuria from day 3 (4.26 ± 0.98 mg/18h, P<0.01; 198.73 ± 21.22 mg/18h at day 17, P<0.001), high serum PCSK9 levels from day 7 (60.427 ± 73.33 ng/ml, P<0.05; 1,404.96 ± 280.29 ng/ml at day 17, P<0.001), and hypercholesterolemia from day 7 (184.49 ± 7.98 mg/dL, P<0.001; 352.58 ± 29.16 mg/dL at day 17, P<0.001). PCSK9 protein and gene expression increased in the kidney but not in the liver at the same time points studied. Conclusion: As PHN rats develop NS, PCSK9 protein level increases in the kidney, but not in the liver. CCD-PCSK9 may play a role in the initiation of hypercholesterolemia in MN-related NS. CCD-PCSK9 could become a new therapeutic target to prevent development of hypercholesterolemia in NS patients in which prolonged hypercholesterolemia may worsen kidney disease and increase risk of cardiovascular disease. Funding: NIDDK Support
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".