Podocyte Injury in Human Primary Membranous Nephropathy: Evidence Supporting a Role for Complement
Bibliographic record
Abstract
Background: Primary membranous nephropathy (PMN) is the leading cause of nephrotic syndrome in adults and a common cause of end-stage kidney disease (ESKD). The Heymann’s nephritis rat model of PMN shows that proteinuria is complementmediated. However, the pathogenetic role of complement in human PMN remains unclear. We aim to demonstrate that complement activation can have both structural and functional effects on podocytes. Methods: An in-vitro model of immortalized human podocytes (from Moin Saleem, Bristol, UK) was used for all the experiments. Cells were exposed to 25% serum of 19 PMN patients (from the Toronto Glomerulonephritis Registry). Complement deposition was detected by immunofluorescence (IF). As positive control, cells were pre-sensitized with anti-CD59 and exposed to 25% normal human serum (NHS) to induce complement activation. Changes in intracellular calcium were monitored using a fluorescent dye (Fluo 8-AM), acquiring images every 20 seconds (up to 10 minutes) by confocal microscopy. Calcium effects on mitochondrial membrane potential were measured by flow cytometry. Intracellular adenosine triphosphate (ATP) changes were analyzed by bioluminescence. Actin cytoskeleton re-arrangements were evaluated by IF. Wound healing assays were performed to study functional effects on cell migration. Results: Incubation with 25% PMN serum led to deposition of both C3b and C5b9 on the cell surface, which was significantly higher compared to controls (p < 0.05). Complement activation induced a significant rise in the intracellular calcium levels. Loss of mitochondrial membrane potential was also observed, together with intracellular ATP decrease, disruption of the actin cytoskeleton and impaired cell migration. Effects of both structure and function of podocytes were reversed by inhibition of the terminal complement pathway. Conclusions: Complement is active in PMN, leading to both structural and functional effects on podocytes. Effects can be reversed by inhibition of the terminal complement pathway. Further studies are needed to fully understand the consequences of complement activation on the podocyte energy machinery and the rationale for the use of complement inhibitors in PMN. Our research may identify novel molecular treatment targets with the potential of improved patient outcomes and quality of life.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.004 | 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".