Calcium-Sensing Receptor in the Thick Ascending Limb and Renal Response to Hypercalcemia
Bibliographic record
Abstract
Key Points The thick ascending limb (TAL) calcium-sensing receptor (CaSR) was critical for controlling calcium excretion in response to hypercalcemia but did not alter urinary magnesium excretion. CaSR activation increased urinary calcium excretion by strongly reducing calcium permeability in the TAL. Activation of the CaSR did not affect the driving force generated by transcellular NaCl transport across the TAL. Background The parathyroid calcium-sensing receptor (CaSR) controls the release of parathyroid hormone in response to changes in serum calcium levels. Activation of the renal CaSR increases urinary calcium excretion and is particularly important when CaSR-dependent reductions in parathyroid hormone fail to lower serum calcium. However, the role of the renal CaSR in protecting against hypercalcemia and the direct effects of chronic CaSR activation on tubular calcium handling remain to be fully elucidated. Methods Experimental hypercalcemia was induced using a vitamin D analog (dihydrotachysterol) in mice with Ksp -Cre–dependent deletion of the Casr ( Ksp - Casr ) in the kidney, with Cre-negative littermates serving as controls (here denoted wild-types [WT]). Urinary and fecal electrolyte determinations, dual-energy x-ray absorptiometry, molecular and biochemical evaluation, and in vitro tubule microperfusion were performed in both sexes. Results Ksp -Cre–driven Casr deletion strongly reduced CaSR abundance in the thick ascending limb (TAL). At baseline, no marked differences were detected in electrolyte handling and tubular permeability characteristics across the TAL. Three days of dihydrotachysterol administration induced hypercalcemia in both WT and Ksp - Casr mice. However, although WT mice developed hypercalciuria, this response was absent in Ksp - Casr mice. Urinary excretion of magnesium and other electrolytes did not differ between hypercalcemic WT and Ksp - Casr mice. Intestinal electrolyte absorption was comparable between the two groups. Microperfusion of isolated cortical TALs revealed no baseline differences in transepithelial voltage, resistance, or ion permeabilities. After hypercalcemia, transepithelial resistance increased and calcium permeability markedly decreased in WT mice, but not in Ksp-Casr mice, with only minor alterations in magnesium permeability and no changes in transepithelial voltage. Conclusions In hypercalcemic mice, the absence of the CaSR in TAL prevented the increase in urinary calcium excretion. The CaSR specifically regulated the paracellular permeability of the TAL, especially for calcium.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".