Cell Surface GRP78 and Integrin β1 Regulate TGFβ1-Mediated Profibrotic Responses 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 proteins. High glucose (HG) induction of glomerular mesangial cell (MC) profibrotic responses play a central role in DKD pathogenesis. We recently showed that the endoplasmic reticulum resident protein GRP78 translocates to the cell surface (csGRP78) in response to HG. Here, with integrin β1 (Intβ1) as its coreceptor, it mediates PI3K/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 its inhibition is not feasible due to adverse effects. Here, we test whether csGRP78/ Intβ1 can regulate TGFβ1 synthesis and activation by HG. Methods: Primary MC were treated with 30mM HG. Standard molecular biology techniques were used for assessment. Results: HG-induced TGFβ1 transcript upregulation and protein secretion were attenuated by specific inhibitory antibodies of either csGRP78 or Intβ1 and with siRNA knockdown of Intβ1. The general integrin activator manganese (Mn) induced TGFβ1 upregulation and interestingly also induced translocation of GRP78 to the cell surface. Mn-induced TGFβ1 synthesis was attenuated by csGRP78 or Intβ1 inhibition. Once secreted, TGFβ1 resides in a latent state. We thus tested whether csGRP78/ Intβ1 facilitated its activation. Inhibition of csGRP78 or Intβ1 as above prevented HG- and Mn-induced TGFβ1 signaling as assessed by activating phosphorylation of its downstream mediator Smad3. Conversely, the Intβ1-activating antibody P4G11 induced both GRP78 cell surface translocation and TGFβ1 signaling. To confirm functionality of TGFβ1 signaling, MC were cocultured with the TGFβ1-responsive mink lung epithelial cells (MLEC) stably expressing a PAI1 promoter luciferase plasmid. HG-induced luciferase activity was attenuated by antibody inhibition of either csGRP78 or Intβ1. Conclusions: These data strongly support a role for csGRP78/Intβ1 in mediating HG-induced TGFβ1 upregulation, activation and profibrotic signaling in MC. Inhibition of csGRP78/Intβ1 signaling thus represents a novel target for attenuating fibrosis in DKD.
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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".