ARHGEF7 (β-PIX) Is Required for the Maintenance of Podocyte Architecture and Glomerular Function
Bibliographic record
Abstract
Significance Statement Dysregulation of Cdc42 and other members of the Rho family of small GTPases in podocytes contributes to the pathogenesis of proteinuria. However, the upstream regulatory mechanisms for Cdc42 activity in podocytes are largely unknown. The authors identified ARHGEF7 (commonly known as β -PIX) as a predominant guanine nucleotide exchange factor and activator of Cdc42 in podocytes. They also demonstrated that β -PIX is required for the maintenance of podocyte architecture and glomerular function via Cdc42 and its downstream effects on Yes-associated protein (YAP) activity. Elucidating the precise details of how numerous regulatory proteins maintain the delicate balance of Rho GTPases in podocytes will be essential in understanding the pathogenesis of proteinuric glomerular diseases and identifying therapeutic targets. Background Previous studies showed that Cdc42, a member of the prototypical Rho family of small GTPases and a regulator of the actin cytoskeleton, is critical for the normal development and health of podocytes. However, upstream regulatory mechanisms for Cdc42 activity in podocytes are largely unknown. Methods We used a proximity-based ligation assay, BioID, to identify guanine nucleotide exchange factors that activate Cdc42 in immortalized human podocytes. We generated podocyte-specific ARHGEF7 (commonly known as β -PIX) knockout mice by crossing β -PIX floxed mice with Podocin-Cre mice. Using shRNA, we established cultured mouse podocytes with β -PIX knockdown and their controls. Results We identified β -PIX as a predominant guanine nucleotide exchange factor that interacts with Cdc42 in human podocytes. Podocyte-specific β -PIX knockout mice developed progressive proteinuria and kidney failure with global or segmental glomerulosclerosis in adulthood. Glomerular podocyte density gradually decreased in podocyte-specific β -PIX knockout mice, indicating podocyte loss. Compared with controls, glomeruli from podocyte-specific β -PIX knockout mice and cultured mouse podocytes with β -PIX knockdown exhibited significant reduction in Cdc42 activity. Loss of β -PIX promoted podocyte apoptosis, which was mediated by the reduced activity of the prosurvival transcriptional regulator Yes-associated protein. Conclusions These findings indicate that β -PIX is required for the maintenance of podocyte architecture and glomerular function via Cdc42 and its downstream Yes-associated protein activities. This appears to be the first evidence that a Rho–guanine nucleotide exchange factor plays a critical role in podocytes.
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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 | 0.001 | 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) | 0.001 | 0.001 |
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".