TGFβ-induced RhoA activation and fibronectin production in mesangial cells require caveolae
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Bibliographic record
Abstract
Glomerular sclerosis of diverse etiologies is characterized by mesangial matrix accumulation, with transforming growth factor-beta (TGFbeta) an important pathogenic factor. The GTPase RhoA mediates TGFbeta-induced matrix accumulation in some settings. Here we study the role of the membrane microdomain caveolae in TGFbeta-induced RhoA activation and fibronectin upregulation in mesangial cells (MC). In primary rat MC, TGFbeta1 time dependently increased RhoA and downstream Rho kinase activation. Rho pathway inhibition blocked TGFbeta1-induced upregulation of fibronectin transcript and protein. TGFbeta1-induced RhoA activation was prevented by disrupting caveolae with cholesterol depletion and rescued by cholesterol repletion. Compared with wild types, RhoA/Rho kinase activation was absent in MC lacking caveolae. Reexpression of caveolin-1 (and caveolae) restored these responses. Phosphorylation of caveolin-1 on Y14, effected by Src kinases, has been implicated in signaling responses. Overexpression of nonphosphorylatable caveolin-1 Y14A prevented TGFbeta1-induced RhoA activation. TGFbeta1 also activated Src, and its inhibition blocked RhoA activation. Furthermore, TGFbeta1 led to association of RhoA and caveolin-1. This was prevented by Src or TGFbeta receptor I inhibition, and by caveolin-1 Y14A overexpression. Last, fibronectin upregulation by TGFbeta1 was blocked by Src inhibition, not seen in caveolin-1 knockout MC, and restored by caveolin-1 reexpression in the latter. TGFbeta1-induced collagen I accumulation also required caveolae. TGFbeta1-mediated Smad2/3 activation, however, did not require caveolae. We conclude that RhoA/Rho kinase mediates TGFbeta-induced fibronectin upregulation. This requires caveolae and caveolin-1 interaction with RhoA. Interference with caveolin/caveolae or RhoA signaling thus represents a potential target for the treatment of fibrotic renal disease.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| 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 it