Myocardin-Related Transcription Factor (MRTF) in Kidney Fibrosis and Its Cross-Talk with Sox9
Bibliographic record
Abstract
Background: Our previous work has shown that the RhoA/F-actin-regulated transcriptional coactivator MRTF plays a key role in the pathogenesis of experimental kidney fibrosis in obstructive nephropathy and polycystic kidney disease. Indeed, MRTF is a central inducer of the profibrotic epithelial phenotype (PEP) upon tubular injury. Further, recent studies implicated Sox9 as a major driver of both kidney regeneration and fibrosis. Interestingly, myocardin, a muscle-specific relative of MRTF, and Sox9 were shown to inhibit each other in vascular smooth muscle cells. Accordingly, the goal of the current studies was twofold: We wished to 1) discern if MRTF and MRTF-inducible genes are enriched in experimental and clinical kidney disease in the tubular epithelium; 2) study the interplay between MRTF and Sox9. As fibrosis requires a switch between normal and maladaptive repair, we wondered if these two fibrogenic transcription factors might control each other’s activity. Methods: We performed scRNASeq meta-analysis on a mouse AKI dataset, and on the human KPMP AKI and CKD databases (1). The interplay between MRTF and SOX9 was followed in tubular cells (LLC-PK1, HEK), using a variety of biochemical/transcriptional assays as indicated at the corresponding results (2). Results: 1) In AKI, MRTF and its targets (e.g. Myh9, ITGB1) were enriched in injured (Kim1+) tubular cells. In human CKD, increased MRTF expression was observed in a subcompartment of the injured proximal tubular cell cluster. Importantly, the correlation among MRTF target genes differed in healthy controls vs CKD patients. In CKD, two new clusters emerged, one of which overlapped with Sox9 targets, while the other was independent. 2) Endogenous or heterologously expressed MRTF and Sox9 bound each other as shown by co-immunoprecipitation. MRTF silencing or KO increased Sox9 expression, while Sox9 had no impact on MRTF expression. Sox9 overexpression inhibited MRTF-induced transcription (SMA promoter-Luc) and SMA expression. Conversely, MRTF overexpression reduced Sox9-driven transcription (4XCol2A1-Luc). Conclusion: Thus, enhanced tubular MRTF signaling is a significant feature in AKI and clinical CKD. Moreover, MRTF and Sox9 interact and inhibit each other’s activity in a cellular setting. The pathophysiological significance of their crosstalk in the fibrogenic epithelium requires future studies.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".