G protein α<sub>12</sub>(Gα<sub>12</sub>) is a negative regulator of kidney injury molecule-1-mediated efferocytosis
Bibliographic record
Abstract
Kidney injury molecule-1 (KIM-1) is a receptor for the “eat me” signal, phosphatidylserine, on apoptotic cells. The specific upregulation of KIM-1 by injured tubular epithelial cells (TECs) enables them to clear apoptotic cells (also known as efferocytosis), thereby protecting from acute kidney injury. Recently, we uncovered that KIM-1 binds directly to the α-subunit of heterotrimeric G 12 protein (Gα 12 ) and inhibits its activation by reactive oxygen species during renal ischemia-reperfusion injury (Ismail OZ, Zhang X, Wei J, Haig A, Denker BM, Suri RS, Sener A, Gunaratnam L. Am J Pathol 185: 1207–1215, 2015). Here, we investigated the role that Gα 12 plays in KIM-1-mediated efferocytosis by TECs. We showed that KIM-1 remains bound to Gα 12 and suppresses its activity during phagocytosis. When we silenced Gα 12 expression using small interefering RNA, KIM-1-mediated engulfment of apoptotic cells was increased significantly; in contrast overexpression of constitutively active Gα 12 ( QLGα 12 ) resulted in inhibition of efferocytosis. Inhibition of RhoA, a key effector of Gα 12 , using a chemical inhibitor or expression of dominant-negative RhoA, had the same effect as inhibition of Gα 12 on efferocytosis. Consistent with this, silencing Gα 12 suppressed active RhoA in KIM-1-expressing cells. Finally, using primary TECs from Kim-1 +/+ and Kim-1 −/− mice, we confirmed that engulfment of apoptotic cells requires KIM-1 expression and that silencing Gα 12 enhanced efferocytosis by primary TECs. Our data reveal a previously unknown role for Gα 12 in regulating efferocytosis and that renal TECs require KIM-1 to mediate this process. These results may have therapeutic implications given the known harmful role of Gα 12 in acute kidney injury.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.003 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".