Mechanisms Underlying the Induction of a Profibrotic Epithelial Phenotype During Renal Fibrosis
Bibliographic record
Abstract
Tubulointerstitial fibrosis (TIF) is the final common pathway through which Chronic Kidney Disease (CKD), a currently incurable condition affecting 12% of the population, progresses toward renal failure. Tubular injury is a key feature of TIF but the exact role of the epithelium in renal fibrosis remains a matter of debate. While tubular cells have the capacity to transdifferentiate to myofibroblasts via epithelial‐mesenchymal/myofibroblast transition (EMT/EMyT), in vivo only a small subset of myofibroblasts appears to originate from the epithelium. The emerging view is that the injured epithelium is a critical driver of fibrogenic processes via acquiring a profibrotic epithelial phenotype (PEP), characterized by robust cytoskeletal remodeling, a change in oxidative state (ROS production), and enhanced secretion of fibrogenic cytokines. These factors in turn prime interstitial cells, initiating fibroblast‐myofibroblast transition. We have previously shown that two major cytoskeleton‐ and TGFβ‐regulated transcriptional coactivators, myocardin‐ related transcription factor (MRTF) and the Hippo pathway effector TAZ are critical contributors to EMyT. Further, both MRTF and TAZ (and its paralog YAP) have been implicated in organ fibrosis; however, the role of these factors in epithelial reprogramming has not been clarified. We therefore hypothesized that 1) MRTF and TAZ are modulated during fibrogenesis in the epithelium, and 2) they are critical mediators of PEP induction. To test these assumptions we used a) LLC‐PK1 proximal tubular cells challenged by fibrogenic mechanical (cell contact uncoupling, mechanical stretch) and chemical (TGFβ) stimuli; and b) unilateral ureteral obstruction (UUO), a mouse model of kidney fibrosis. Here we show that fibrogenic stimuli 1) induced robust nuclear translocation of MRTF and TAZ in tubular cells and 2) provoked massive upregulation of TAZ mRNA and protein in the epithelium both in vitro and in vivo . The latter effect was verified in tubular samples isolated by laser capture microdissection. Pharmacological or siRNA‐mediated inhibition of MRTF prevented TAZ upregulation indicating a hierarchy between these factors. PEP was associated with a substantial increase in the expression of NADPH oxidase 4 (Nox4), key determinant of the epithelial redox state. Pharmacological or genetic inhibition of MRTF or TAZ/YAP prevented the increase in Nox4 expression in LLC‐PK1 cells. Moreover, treatment of mice with TAZ/YAP inhibitor verteporfin suppressed the UUO‐induced rise in tubular Nox4. Fibrogenic stimuli induced epithelial expression of connective tissue growth factor (CTGF), which was dependent both on MRTF and TAZ/YAP. These stimuli also provoked tubular production of PDGF‐B, Indian Hedgehog and TGFβ. Studies are underway to determine the role of MRTF and TAZ/YAP in the production of these fibrogenic cytokines. In conclusion, we have shown that MRTF and TAZ are critical mediators of PEP during fibrogenesis. Support or Funding Information Kidney Foundation of Canada
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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 | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".