Plasma membrane depolarization‐induced ERK activation: role in regulating paracellular permeability of the proximal tubular epithelium
Bibliographic record
Abstract
Both physiological and pathological conditions, including apical ion transport, hypoxia, oxidative stress, and ATP depletion can alter the membrane potential of epithelial cells. We have previously shown that membrane depolarization induces Rho‐Rho kinase (ROK) mediated phosphorylation of myosin light chain (MLC) in proximal tubule epithelial cells and elevates paracellular permeability. Here we show that the permeability increase was absent in cells stably expressing a non‐phosphorylatable, dominant negative MLC. Depolarization, elicited by high extracellular [K + ],– or ouabain, an inhibitor of the Na + /K + ATPase, also activated the Ras‐Raf‐MEK‐ERK pathway. ERK activation was fast, reversible and independent of intracellular Ca 2+ . Immunofluorescent staining revealed that ERK translocates to the cell periphery. The MEK inhibitor PD98059 reduced the depolarization‐induced rise in paracellular permeability. Interestingly, PD98059 also mitigated the depolarization‐induced MLC phosphorylation, raising the possibility that ERK affects paracellular permeability by contributing to increased contractility. In summary, our data suggest that cell contractility, regulated by the Rho‐ROK and the Ras‐ERK pathway might play a key role in epithelial barrier dysfunction caused by sustained depolarization. Support: NSERC, Banting Foundation and Kidney Foundation of Canada.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".