Differential Expression of Renal and Hepatic PCSK9 During Development of Hypercholesterolemia in the Puromycin Aminonucleoside Nephrosis Rat Model of Nephrotic Syndrome
Bibliographic record
Abstract
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) Conclusions: 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
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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) | 0.000 | 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".