Atorvastatin does not ameliorate lithium‐induced nephrogenic diabetes insipidus in mice
Bibliographic record
Abstract
Lithium (Li) is an important mood‐stabilizing drug used in the treatment of affective disorders. However, as a significant adverse effect patients can develop Nephrogenic Diabetes Insipidus (NDI). NDI is characterized by the inability of the kidney to concentrate urine in response to vasopressin, resulting in severe polyuria and an increased long‐term risk of chronic kidney disease. Li‐NDI is associated with downregulation of the water channel AQP2 and a cellular remodeling of the kidney collecting duct. Effective and safe treatment of Li‐NDI is still lacking. Statins are cholesterol‐lowering drugs, which appear to increase AQP2 membrane‐translocation and improve urine concentration ability in other NDI models. This project will investigate if atorvastatin is able to prevent the Li‐induced changes in mice using a mouse cortical collecting duct cell line (mCCD) and C57BL/6 mice. Biotinylation assays showed that acute (1hr) treatment with simvastatin (p<0.05) or fluvastatin (p<0.0001) increased AQP2 membrane accumulation compared to controls in the mCCD cells. This confirms that the mCCD cell line respond to acute statin treatment as shown before for these two statins in other cellular and animal models. In order to see whether chronic statin treatment abolish the effects of Li, cells were treated with Li and Li/atorvastatin for 48 hrs. Li reduced total AQP2 levels (p<0.01) compared to controls as expected, but combined Li/atorvastatin treatment did not prevent the Li‐induced downregulation of AQP2. Chronic (21 days) Li treatment of mice increased urine output (p<0.0001) and reduced urine osmolality (p<0.0001) compared to controls (receiving normal food). Atorvastatin (given in combination with Li for 21 days) decreased levels of triglycerides in the blood (p<0.05) compared to controls. Combined Li/atorvastatin treatment did not prevent the effects of Li on urine output and urine osmolality. In kidney inner medulla, western blotting showed that Li reduced total AQP2 levels (p<0.001) and increased pS261‐AQP2 levels (p<0.05), and further showed a tendency to pERK1/2 upregulation (p=0.06) compared to controls as shown previously. However, combined Li/atorvastatin treatment did not abolish any of these changes. Immunohistochemistry further showed that atorvastatin did not prevent the Li‐induced increase in intercalated cells and increased proliferation in the inner medulla. In conclusion, both chronic in vitro and in vivo experiments showed that atorvastatin does not appear to have positive effects on prevention of Li‐NDI in mice. Support or Funding Information Danish Medical Research Council, Beckett Fonden, Aase and Ejnar Danielsens Fonden, Knud and Edith Eriksens Mindefond This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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) | 0.000 | 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".