High-Fat Feeding in Pkd1 RC/RC Mice Associates With Upregulation of Havcr1 and Immune Activation
Bibliographic record
Abstract
Background: Autosomal dominant polycystic kidney disease (APDKD) is the most common inherited nephropathy worldwide and an important cause of end-stage renal disease. The effects of overweight on ADPKD are unclear, although recent clinical research suggests increased body mass index might be an independent risk factor for disease severity. In addition, high-fat feeding aggravated cystic disease in two orthologous mouse models of ADPKD, possibly in association with impaired fatty acid oxidation in the cystic epithelium. We explored the effects of a high-fat diet (HFD) in young Pkd1 RC/RC mice, a hypomorphic model of ADPKD characterized by slow progression of cystic disease similarly to human ADPKD. Methods: Since Pkd1 RC/RC mice exhibit sexual dimorphism, with females showing more severe cystic disease, we assigned 20 females and 20 males in a 1:1 ratio to either a HFD, with 60% of calories derived from fat, or a carbohydrate-rich “normal diet” (ND), with 10% of calories derived from fat. Mice were started on the diets at 2 months of age and sacrificed at 7 months of age. We then assessed kidney weight and volume, histology and histomorphometry, biochemistry, and gene expression. In addition to microarray analysis, we performed gene-set enrichment using Enrichr. Results: HFD compared to ND feeding associated with increased kidney volume (p<0.0001) and cystic index (p=0.001) in females, but it did not associate with reduced kidney function. In the kidneys of females fed a HFD compared to a ND, we identified: (1) upregulation of Havcr1 (FDR p=0.0009), a pro-inflammatory biomarker of renal tubular injury; (2) enrichment in pathways involved in innate and adaptive immunity, with a majority of these genes upregulated in our dataset; (3) enrichment in EP300 (adjusted p=8.7*10-21), a transcriptional co-activator of cell proliferation, which was upregulated in our dataset; (4) enrichment in PPARα (adjusted p=8.5*10-10), a major regulator of fatty acid oxidation, which was downregulated in our dataset; and (5) evidence of macrophage accumulation on immunohistochemistry (p=0.07). Conclusions: HFD feeding in female Pkd1 RC/RC mice aggravated the kidney cyst burden, in association with a transcriptomic profile suggesting early-stage inflammatory kidney injury and inhibited fatty acid oxidation. Funding: Government Support - Non-U.S.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".