Global but Not Tubule Cell-Specific Knockout of STING Attenuates Kidney Injury in Mice with Unilateral Ureteral Obstruction
Bibliographic record
Abstract
Background: Recent studies have identified a key role for the inflammatory mediator STING in kidney injury. Because it is activated by the cellular response to displaced DNA, it has been proposed that STING mediates kidney injury when mitochondrial DNA leaks into the cytosol of damaged tubule epithelial cells. However, STING is not specific to tubule cells, also having an important regulatory function in other cell-types, amongst them immune cells. Here, we compared the effects of deletion of STING from tubule cells with the effects of global STING deletion in mice with kidney injury caused by unilateral ureteral obstruction (UUO). Methods: Experimentswere performed in wildtype mice, Stingfl/fl mice, Pax8Cre+Stingfl/fl mice (tubule cell-specific STING knockout mice; STINGTubKO) and global STING knockout mice (STINGKO) 14 days after sham surgery or UUO. Results: mRNA and protein levels of STING were both increased >5-fold in mice after UUO. In situ hybridization and immunostaining confirmed presence of STING in damaged tubule cells, occasional glomerular cells and notably in infiltrating interstitial cells in UUO kidneys. Knockout of STING was confirmed in STINGKO mice by immunoblotting; and in STINGTubKO mice by immunohistochemistry 24h after ischemia reperfusion injury. Kidney injury was then determined by measuring mRNA levels of Havcr1, the gene encoding KIM-1, in control (Stingfl/fl) mice, STINGTubKO mice and STINGKO mice 14 days after UUO or sham surgery. Havcr1 mRNA levels were increased >120-fold in Stingfl/fl mice after UUO and they were unaffected by tubule-cell specific STING knockout. In contrast, Havcr1 mRNA levels after UUO, while increased >60-fold in global STING knockout mice, and were significantly lower than in Stingfl/fl and STINGTubKO mice after UUO (P<0.01). Conclusion: Kidney injury in UUO mice, as assessed by Havcr1 mRNA levels, is attenuated by global STING deficiency rather than tubule cell-specific STING deficiency. These findings indicate that the actions of STING in kidney disease extend beyond mediating the response to mitochondrial damage in tubule cells. The effects of STING may be primarily due to its actions in other cell-types, especially in infiltrating immune cells. Funding: Government Support – Non-U.S.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".