Bibliographic record
Abstract
Mechanism(s) responsible for the progression of chronic kidney disease (CKD) to end stage renal disease have not been fully elucidated. During my Ph.D. studies I completed bioinformatic, in vitro, in-silico, and in vivo studies to address this gap in current knowledge.In a first series of experiments, microarray analysis of kidneys from Col4a3-/- mice, an experimental model of CKD, revealed an early increase in follistatin-like-1 (FSTL1) expression. Little is known about FSTL1 in experimental or human CKD. FSTL1 localized to interstitial cells by RNAscope® and single cell transcriptomic data from human CKD showed that FSTL1 was confined to fibroblasts/myofibroblasts. In vitro, FSTL1 activated AP1 and NFκB, increased collagen I and interleukin-6 expression, and induced apoptosis in kidney cells. FSTL1 expression in kidneys from humans with CKD associated with age, eGFR, and proteinuria and was also related to interstitial fibrosis and tubular atrophy. Remarkably, CKD progression in participants with FSGS from the Nephrotic Syndrome Study Network (NEPTUNE) study was greater in patients with high baseline FSTL1 mRNA levels. Angiotensin-converting enzyme 2 (ACE2) catalyzes conversion of angiotensin (Ang) II to Ang-(1–7). It is decreased in kidneys from Col4a3–/– mice and recombinant ACE2 (rACE2) administration lessens kidney injury in these mice. Interestingly, ACE2 is a receptor for SARS-CoV-2 but little is known about renal ACE2 expression in human CKD. I accessed renal tubulointerstitial (TI) and glomerular microarray expression data and clinical variables from healthy living donors and patients with CKD from the European Renal cDNA Bank. ACE2 expression was greater in males than females and lower in the glomeruli. Genes involved in inflammation and fibrosis correlated inversely with ACE2 expression. I then studied ACE2 expression in participants with FSGS from NEPTUNE. ACE2 expression was related to both sex and eGFR in this cohort. ACE2 expression was inversely related to kidney interstitial fibrosis, and tubular atrophy, in males but not in females. In summary, my studies support the hypotheses that intrarenal FSTL1 and low ACE2 contribute to the progression of CKD, suggesting that they may be important targets for the development of new treatment approaches to CKD.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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".