Role of KIM-1 and TBX1 in AKI to CKD Transition
Bibliographic record
Abstract
Background: Acute kidney injury (AKI) affects 20% of hospitalized patients. The most common cause is renal ischemia-reperfusion injury (IRI). Patients who survive mild-to-moderate AKI often have complete renal recovery, but severe AKI can progress to the development of chronic kidney disease (CKD). Kidney Injury Molecule-1 (KIM-1) is a transmembrane receptor expressed by proximal tubular epithelial cells (PTECs) during injury. Notwithstanding that, severe AKI leads to persistent KIM-1 expression and drives renal fibrosis. Using microarray analysis, we identified T Box-1/TBX1 as a potential KIM-1 regulated gene that may mediate its maladaptive effects during severe AKI. Methods: KIM-1+/+ and KIM-1-/- C57BL/6 mice were subjected to sevre unilateral ischemia reperfusion injury (UIRI) by clamping the renal artery for 55 minutes. Kidneys were isolated after 7 and 42 days of reperfusion to assess histology and, markers of injury and fibrosis. RNA sequencing of kidneys from the KIM-1+/+ and KIM-1-/- mice after 55 min UIRI was performed. In order to assess the fibrogenic potential of TBX1 in vivo, Tamoxifen-inducible PTEC-specific TBX1 knockout (TBX1ptKO) mice were generated. In vitro model for gain of TBX1 function was created by using primary PTECs isolated from murine cortical kidney subjected to biochemical and functional assays. Results: Compared to the ipsilateral kidneys from KIM-1-/- mice, the kidneys from KIM-1+/+ mice were markedly shrunken and fibrotic at 42 days after UIRI. We also observed a significant upregulation of mRNA encoding a panel of pro-inflammatory cytokines and growth factors at both 7 and 42 days after UIRI in KIM-1+/+ kidney compared to KIM-1-/- kidneys. Primary PTECs isolated only from KIM-1+/+ kidneys significantly increased the chemotaxis of Raw macrophages whereas KIM-1+/+ PTECs became arrested at the G2/M phase of the cell cycle, and adopted a senescent phenotype. Conditional silencing of KIM-1 was associated with a significant reduction in TBX1 expression at both mRNA and protein levels. TBX1 expression profile positively correlated with fibrosis in KIM-1+/+ mice exposed to severe IRI. TBX1 enhanced PTEC migration, acquisition of a senescence phenotype, production of extracellular matrix and profibrotic factors. Conclusions: Our results suggest that sustained KIM-1 expression following severe AKI may drive murine kidney fibrosis due to activation of TBX1. 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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".