Cell Surface GRP78 Regulates TGF-β1-Mediated Profibrotic Responses via TSP-1 in Diabetic Kidney Disease
Bibliographic record
Abstract
Background: Diabetic kidney disease (DKD) is the leading cause of kidney failure in North America, characterized by glomerular accumulation of extracellular matrix (ECM) proteins. High glucose (HG) induction of glomerular mesangial cell (MC) profibrotic responses plays a central role in its pathogenesis. We recently showed that the endoplasmic reticulum resident GRP78 translocates to the cell surface in response to HG, where it mediates Akt activation and downstream profibrotic responses in MC. Transforming growth factor β1 (TGFβ1) is recognized as a central mediator of HG-induced profibrotic responses, but whether it is regulated by cell surface GRP78 (csGRP78) is unknown. TGFβ1 is stored in the ECM in a latent form, requiring release for biological activity. The matrix glycoprotein thrombospondin-1 (TSP-1) is an important factor in TGFβ1 activation, known to be increased in DKD and by HG in MC. Here we determined whether csGRP78 regulates the expression of TSP-1 and thereby TGFβ1 activation in HG. Methods: Primary rat and mouse MC were treated with 30mM HG. TSP-1 upregulation and deposition into the ECM and TGFβ1 activation were assessed using standard molecular biology techniques. Results: TSP-1 transcript and promoter activity were increased by HG, as were cellular and ECM TSP-1, and these required PI3K/Akt activity. To determine whether csGRP78 was required, its activity was inhibited using vaspin or the C-terminal targeting antibody C38. Alternatively, GRP78 translocation to the cell surface was prevented with siRNA downregulation of its transport chaperone MTJ-1. All of these prevented HG-induced TSP-1 upregulation and deposition into the ECM. The HG-induced increase in active TGFβ1 in the medium was also inhibited, and this was associated with reduced intracellular Smad3 activation and signaling. Conclusions: These data support an important role for csGRP78 in regulating HG-induced TSP-1 transcriptional induction via PI3K/Akt signaling. Functionally, this enables TGFβ1 activation in response to HG, with consequent increase in ECM proteins. Means of inhibiting csGRP78 signaling represent a novel target for preventing the DKD-associated fibrosis. TGFβ1 is a central mediator of DKD, but its inhibition is not feasible due to adverse effects. Thus, indirect methods of attenuation are of current interest. 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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 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".