Protective Effect of GIT2 against Podocyte Injury in Mice
Bibliographic record
Abstract
Background: Podocytes have an intricate structure featured by numerous actin-based projections called foot processes (FP). Rho GTPases, including Rac1, play important roles in actin cytoskeletal remodeling required for cell morphology and adhesion. We previously showed that Rac1 activation in podocytes causes FP effacement and proteinuria, but the upstream regulatory mechanism directing Rac1 is largely unknown. Recently, we identified focal adhesion protein GIT2 as one of the Rac1-interacting proteins in immortalized human podocytes, and showed that GIT2 knockdown elicited Rac1 activation. Methods: The protein and mRNA expression of GIT2 in mice kidney were studied by immunoblotting and in situ hybridization, respectively. Git2-floxed mice were established using CLICK (CRISPR with long single-stranded DNA inducing conditional knockout alleles). They were then crossed with NPHS2-Cre mice to generate podocyte-specific Git2 knockout (KO) mice. KO mice and age-matched controls were subjected to the minimal change disease model by lipopolysaccharide (LPS) or the salt-sensitive hypertension model by uninephrectomy (UNx) with deoxycorticosterone acetate (DOCA)/salt. Results: GIT2 was relatively enriched in glomeruli including podocytes in the kidney. In KO mice, glomerular expression of GIT2 protein was significantly reduced compared with controls. When challenged with LPS, KO mice showed sustained high levels of proteinuria, resulting in a significantly higher urine albumin to creatinine ratio (ACR) at 48hours compared with controls. When treated with UNx-DOCA/salt, systolic blood pressure was increased similarly at day14 in both KO and control mice. While UNx-DOCA/salt induced a significant increase of ACR in both mouse groups, KO mice tended to have more severe proteinuria. Rac1 inhibitor NSC23766 significantly decreased ACR in UNx-DOCA/salt-treated KO mice. Serum UN was significantly increased in UNx-DOCA/salt-treated KO mice compared with controls. In both LPS and UNx-DOCA/salt models, FP effacement was exacerbated in KO mice compared with controls. Conclusion: In the current study, we demonstrated that GIT2 protects podocytes and glomerular function against injury. GIT2 may become a new therapeutic target on the Rac1 pathway in podocytopathy.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".