mTOR Inhibition: A Novel Regulator of Soluble CD89 Activity via the Mesangial Transferrin Receptor and Its Therapeutic Potential in IgA Nephropathy
Bibliographic record
Abstract
Background: IgA nephropathy (IgAN) is the predominant primary glomerulonephritis worlwide. We have recently shown that soluble IgA receptor CD89 induces mesangial cell proliferation via the PI3K/Akt/mTOR axis (Cambier, Kidney Int 2022). Transferrin receptor (TfR), an IgA1 receptor overexpressed in mesangium, is associated with IgAN progression (Tamouza, Kidney Int 2012). sCD89 binds also to TfR (Berthelot, J Exp Med 2012). As mTOR is involved in sCD89-TfR signaling, we explore its inhibitor, the everolimus, in a IgAN model, the α1KICD89Tg mouse, that express human IgA1 and CD89. Single-cell kidney biopsy techniques were used to delve TfR1 and mTOR expression in mesangial cells from IgAN patients. Methods: 20 adult α1KICD89Tg and 6 young rCD89-injected α1KI mice constituted two groups. Treated arms received everolimus (2 mg/kg) for 8 weeks or 4 weeks, respectively, while the control arms underwent a placebo water. Weekly urine collections monitored proteinuria and mice were sacrificed for renal function, immune complex analysis, and histological examination. PI3K/Akt/mTOR activation under sCD89 stimulation was studied with human mesangial cells. Single cell analysis were performed to quantify mTOR and TfR1 expression in 5 patient kidney biopsy and 1 healthy kidney tissue. Results: Everolimus treatment showed a reduction in mesangial TfR expression, IgA1 and C3 deposits in kidneys of both groups (p<0.001, respectively). It also decreased cell proliferation, as indicated by Ki67 staining in glomeruli (p<0.05). This treatment led to decreased proteinuria (p<0.05). Levels of immune complexes (sCD89-IgA1, IgG-IgA1) were impaired by everolimus treatment. Rec sCD89 induced activation of PI3K/Akt/mTOR pathway in human mesangial cells. Using single cells from kidney biopsies we found overexpression of TfR1 and mTOR in mesangial cells from IgAN patient biopsies but not in healthy kidney. Conclusion: mTOR inhibitor prevents and treats IgAN in a pre-clinical model. These results open new avenues for future clinical trials in IgAN. 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".