Integrative Systems Analyses Reveal Calcineurin Inhibitor-Mediated Control of Human Podocyte Biophysics and Physiology
Bibliographic record
Abstract
Background: Calcineurin inhibitors (CNIs), such as cyclosporine A (CsA), tacrolimus (TAC), and voclosporin (VCS), have been used to regulate the immune response in a number of conditions, including kidney transplantation, lupus nephritis and other autoimmune disorders. Whereas the immunosuppressive functions of CNIs are regulated by the calcium-calmodulin pathway, the mechanisms by which they control glomerular cell biology remain elusive. We previously showed that CsA treatment in LPS-induced proteinuria was associated with cytoskeletal stabilization of podocytes leading to preserved glomerular integrity. Methods: We combine network, enrichment and pathway analyses of transcriptomics, isobaric-tagged quantitative phospho- and total proteomics, atomic force microscope elastography and high content image analytics with classical cell biological assays to understand the role of CNIs in podocyte biology and biomechanics. Results: We discovered that podocyte physiology is significantly modulated by all CNIs, and that this regulation converged on the cytoskeletal architecture. Divergent phosphoproteomic signatures highlighted the differential impact of each drug in microtubule organization, post-translational modifications, and histone methylation. Downstream gene transcription showed a significant upregulation of focal adhesion molecules, GEF/GAPs and cytoskeletal-adhesion organizers. Our phoshoproteomic observations recapitulated several previously known targets, such as synaptopodin, and detected a number of novel cytoskeletal posttranslational modifications. Interestingly, we observed that at maximal clinically relevant concentrations lower than CsA and TAC, VCS affected these signaling pathways for enhancing cytoskeletal stability, which is confirmed via focal adhesion morphometrics, spreading area and cellular elasticity. Conclusion: Based on these findings, our study contributes significantly to the understanding of the role of CNIs in podocyte function, independently from other cell biological impacts, and it represents an integrative cellular and molecular atlas to guide the discovery of novel drug-induced modulators of glomerulopathies and evaluate the effect of new CNIs on podocyte biophysical and biomechanical features. Funding: Commercial Support - Aurinia Pharmaceuticals
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".