Cell Surface GRP78 and α2M* Are Important Mediators of Tubulointerstitial Fibrosis in CKD
Bibliographic record
Abstract
Background: Diabetic kidney disease (DKD) is characterized by glomerular accumulation of extracellular matrix (ECM) proteins followed by the development of tubulointerstitial fibrosis. We recently showed the endoplasmic reticulum resident GRP78 translocates to the cell surface (csGRP78) in response to HG, promoting profibrotic responses in mesangial cells. We further implicated activated alpha 2 macroglobulin (α2M*) as an activator of csGRP78 signaling. Based on increased expression of this receptor-ligand pair in both DKD and non-diabetic chronic kidney disease (CKD) mouse models, we thus wanted to elucidate this signaling pathway's influence on other cell types relevant to kidney disease (proximal tubule epithelial cells (PTEC) and renal fibroblasts (RF)) as well as a potential role for TGFβ1-induced signaling. Methods: PTEC and RF were treated with 30mM HG or 5ng/mL TGFβ1 plus csGRP78 or α2M* inhibitors. Standard molecular biology techniques were used for assessment. Immunohistochemistry staining was conducted on kidney tissues from mouse models of DKD and CKD. Results: We observed increased localization of GRP78 to the surface of PTEC and RF with either HG or TGFβ1 stimulus. Further, α2M expression and activation were shown to be increased by both HG and TGFβ1. Inhibition of either csGRP78 or α2M* prevented HG and TGFβ1-induced ECM production (fibronectin and collagen IV). By HG treatment, downstream TGFβ1 signaling (measured by activation of Smad3) was attenuated by csGRP78 or α2M* inhibition. Interestingly, we observed no effect on Smad3 activation with csGRP78 or α2M* inhibition with TGFβ1 treatment. We hypothesized a potential role for non-canonical TGFβ1 signaling being mediated by csGRP78/ α2M*. We next assessed the known non-canonical TGFβ1 signaling molecules yes associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Here we observed that inhibition of either csGRP78 and α2M* attenuated YAP and TAZ expression under both HG and TGFβ1 treatment. This implicates Smad-dependent and independent signaling being mediated by csGRP78/ α2M*. Conclusions: These data support a role for csGRP78/α2M* in mediating HG or TGFβ1-induced profibrotic signaling in PTEC and RF. Inhibition of this signaling pathway represents a novel target for preventing DKD or CKD-associated fibrosis which we are currently evaluating in vivo. Funding: Government Support - Non-U.S.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| 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".