Gentamicin induces calciuresis by blocking TRPV5
Bibliographic record
Abstract
Background Treatment with the aminoglycoside antibiotic gentamicin can be associated with severe side effects including renal Ca 2+ wasting. The underlying mechanism is unknown but proposed to involve activation of the Ca 2+ ‐sensing receptor (CaSR) in the thick ascending limb (TAL), which would increase expression of claudin‐14 (CLDN14) and limit Ca 2+ reabsorption. However, no direct evidence for this hypothesis has been presented. Methods The effect of gentamicin on renal Ca 2+ handling was studied in vivo using mouse models with impaired Ca 2+ reabsorption in the proximal tubule and TAL. The effects of gentamicin in CaSR activation were studied in vitro using a Cldn14 promoter luciferase‐reporter assay, while the effect of gentamicin on the distal nephron Ca 2+ channel transient potential receptor vanilloid 5 (TPRV5) activity was determined by patch‐clamp in HEK293 cells. Results Gentamicin increased urinary Ca 2+ excretion in wildtype mice following acute and chronic administration. This calciuretic effect was unaltered in mice with genetic CaSR overactivation and remained present in furosemide‐treated animals. Moreover, gentamicin‐induced calciuresis was not significantly different in Cldn14 ‐/‐ mice or mice with impaired proximal tubular Ca 2+ reabsorption ( Cldn2 ‐/‐ mice), compared to wildtype animals. In vitro , gentamicin failed to activate the CaSR. In contrast, patch‐clamp analysis revealed that gentamicin inhibited rabbit and human TRPV5 channel currents in a dose‐dependent manner. In accordance with a direct effect of gentamicin on TRPV5, chronic gentamicin administration downregulated gene expression of distal nephron Ca 2+ transporters in mice. Conclusion We show here that gentamicin does not cause hypercalciuria via activation of the CaSR‐CLDN14 pathway or by interfering with proximal tubular CLDN2‐dependent Ca 2+ reabsorption. Instead, gentamicin blocks distal Ca 2+ reabsorption by direct inhibition of the Ca 2+ channel TRPV5. These findings offer new insights into Ca 2+ wasting in patients treated with gentamicin.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.002 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".