Klotho Prevents Renal Calcium Loss
Bibliographic record
Abstract
Disturbed calcium (Ca(2+)) homeostasis, which is implicit to the aging phenotype of klotho-deficient mice, has been attributed to altered vitamin D metabolism, but alternative possibilities exist. We hypothesized that failed tubular Ca(2+) absorption is primary, which causes increased urinary Ca(2+) excretion, leading to elevated 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and its sequelae. Here, we assessed intestinal Ca(2+) absorption, bone densitometry, renal Ca(2+) excretion, and renal morphology via energy-dispersive x-ray microanalysis in wild-type and klotho(-/-) mice. We observed elevated serum Ca(2+) and fractional excretion of Ca(2+) (FE(Ca)) in klotho(-/-) mice. Klotho(-/-) mice also showed intestinal Ca(2+) hyperabsorption, osteopenia, and renal precipitation of calcium-phosphate. Duodenal mRNA levels of transient receptor potential vanilloid 6 (TRPV6) and calbindin-D(9K) increased. In the kidney, klotho(-/-) mice exhibited increased expression of TRPV5 and decreased expression of the sodium/calcium exchanger (NCX1) and calbindin-D(28K), implying a failure to absorb Ca(2+) through the distal convoluted tubule/connecting tubule (DCT/CNT) via TRPV5. Gene and protein expression of the vitamin D receptor (VDR), 25-hydroxyvitamin D-1-alpha-hydroxylase (1alphaOHase), and calbindin-D(9K) excluded renal vitamin D resistance. By modulating the diet, we showed that the renal Ca(2+) wasting was not secondary to hypercalcemia and/or hypervitaminosis D. In summary, these findings illustrate a primary defect in tubular Ca(2+) handling that contributes to the precipitation of calcium-phosphate in DCT/CNT. This highlights the importance of klotho to the prevention of renal Ca(2+) loss, secondary hypervitaminosis D, osteopenia, and nephrocalcinosis.
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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 | 0.001 |
| 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".