Effect of age on the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 by kidney of rat.

Armbrecht, H. J.; Zenser, Terry V.; Davis, Bernard B.

doi:10.1172/jci109941

Cited by 109 publications

(24 citation statements)

References 21 publications

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“…This can be explained by the age-related decline in kidney function. As kidney function declines in rats, so does 1,25(OH) 2 D production (30) and metabolic clearance of 25(OH)D. Likewise, the most consistent relationship that we saw across adult age groups was that 1,25(OH) 2 D correlated inversely with creatinine (Table 2). Thus, although vitamin D production in the skin decreases with age, so does the utilization of 25(OH)D in the kidney; these effects cancel each other out so that aging per se has no effect on 25(OH)D levels.…”

Section: Discussionsupporting

confidence: 66%

Age-Related Changes in the 25-Hydroxyvitamin D Versus Parathyroid Hormone Relationship Suggest a Different Reason Why Older Adults Require More Vitamin D

Vieth

Ladak²,

Walfish

2003

The Journal of Clinical Endocrinology &Amp; Metabolism

381

230

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Vitamin D requirements are thought to vary with age, but there is little comparative evidence for this. One goal in establishing a vitamin D requirement is to avoid secondary hyperparathyroidism. We studied 1741 euthyroid, thyroid clinic outpatients without evidence of calcium abnormalities, ranging in age from 19 to 97 yr, whose serum and urine had been analyzed for calcium, vitamin D, and parathyroid status. We found no effect of age on the 25-hydroxyvitamin D [25(OH)D] concentration associated with specific vitamin D intakes, and there was no relationship between 25(OH)D and 1,25hydroxyvitamin D [1,25(OH)2D]. In every age group, serum 1,25(OH)2D declined with increasing creatinine (P < 0.001). What changed with age included creatinine, which correlated with 25(OH)D (r = 0.146, P < 0.001) only in the youngest age group (19-50 yr) but not in the older age groups (P > 0.1). Creatinine did not correlate with PTH in the youngest age group, but the relationship became significant as age increased (e.g. for the elderly, r = 0.365, P < 0.001). Linear regression of log PTH vs. log 25(OH)D agreed with the natural shape of the relationship observed with scatterplot smoothing, and this showed no plateau in PTH as 25(OH)D increased. We compared PTH concentrations among age groups, based on 20 nmol/liter increments in 25(OH)D. Mean PTH in adults older than 70 yr was consistently higher than in adults younger than 50 yr (P < 0.05 by ANOVA and Dunnett's t test). PTH levels of the elderly who had 25(OH)D concentrations greater than 100 nmol/liter matched PTH of younger adults having 25(OH)D concentrations near 70 nmol/liter. This study shows that all age groups exhibit a high prevalence of 25(OH)D insufficiency and secondary hyperparathyroidism. Older adults are just as efficient in maintaining 25(OH)D, but they need more vitamin D to produce the higher 25(OH)D concentrations required to overcome the hyperparathyroidism associated with their diminishing renal function.

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Section: Discussionsupporting

confidence: 66%

Age-Related Changes in the 25-Hydroxyvitamin D Versus Parathyroid Hormone Relationship Suggest a Different Reason Why Older Adults Require More Vitamin D

Vieth

Ladak²,

Walfish

2003

The Journal of Clinical Endocrinology &Amp; Metabolism

381

230

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“…The youngest rats (96 g, approximately 4 wk of age) had greater la-OHase activity than all other groups; no differences were apparent between the older groups. This finding is consistent with earlier reports of the age dependence of this enzyme (10). Figure 2 shows the effect of both media calcium and the duration of phosphorus deprivation on renal la-OHase activity.…”

Section: Animalssupporting

confidence: 92%

Media Calcium Attenuates Mitochondrial 1,25(OH)2D Production in Phosphorus or Vitamin D-Deprived Rats

Carpenter

Ellis

1995

Pediatr Res

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Although PTH and hypophosphatemia are the best known stimulators of 25-hydroxyvitamin D-la-hydroxylase, 1,25(OH),D3 production in rats and humans can be modulated by circulating calcium, independent of PTH. To test whether calcium modulates this function directly in mitochondria, we examined effects of calcium on la-hydroxylase in isolated mitochondrial preparations under basal and stimulated conditions. Rats were fed a low phosphorus (or matched control) diet for 4 or 7 d or a vitamin D-deficient (or matched control) diet for 2, 4, or 7 wk. Renal mitochondria were isolated and assayed for la-hydroxylase activity in the presence or absence of added calcium. Calcium did not alter la-hydroxylase in rats on control diets. After 4 d of low phosphorus diet, la-hydroxylase was increased 2-fold over basal activity; media calcium prevented this stimulatory response. By 7 d the calcium effect was not evident. After 4 wk of vitamin D deprivation, activity was -30-fold greater than controls; calcium reduced this response significantly (15-fold). A significant, but less marked inhibition of activity by calcium was present in rats subjected to 7 wk of vitamin D deprivation. Extramitochondrial calcium can directly modulate 1,25(OH),D3 production, but this effect appears to be secondary to the primary physiologic regulators of this function. The calcium effect can be overcome after longer term exposure to phosphorus deprivation, but is sustained in the presence of long term vitamin D deprivation. The best known active metabolite of vitamin D is 1,25(OH),D, which in humans and other mammals, effects numerous physiologic events. Production of 1,25(OH),D is tightly controlled at the final step of its biosynthetic pathway, performed in renal tubular mitochondria by a P450 enzyme system, the renal la-OHase (1). Although several factors have been shown to be trophic for this reaction (e.g. IGF-I, estrogen, thyroid hormone, calcitonin), the predominant physiologic regulators of this reaction in the intact organism are hypophosphatemia and PTH (2). The stimulatory effect of hypocalcemia on 1,25(OH),D production has generally been attributed to resultant secondary hyperparathyroidism (3). In contrast with the view that calcium regulation of la-OHase is entirely dependent on PTH effects, more recent work has shown that extracellular calcium is able to regulate this reaction in rats (4, 5) and humans (6) finding, we examined the ability of calcium to modulate I ) basal enzyme activity and 2) stimulated enzyme activity (using two standard dietary provocations) directly at the mitochondrial level. METHODS Animals.Male Holtzman rats were obtained from Harlan (Madison, WI) at weanling. In experiments examining effects of phosphorus deprivation, rats were housed in our animal facilities and placed on either a low phosphorus diet (Teklad, Madison, WI), containing 0.02% phosphorus, 0.6% calcium and 2200 U of vitamin D/kg, or a control diet containing 0.6% phosphorus, and otherwise matched to the experimental diet.Animals were killed after 4 or...

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“…In aging, as indicated in studies in both animals and humans, there is a decline in the ability of the kidney to synthesize 1,25(OH) 2 D 3 (22,454). We and others have noted that rat renal CYP24A1 increases with age (22,295 …”

Section: F Aging and Renal Vitamin D Hydroxylasesmentioning

confidence: 90%

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Christakos

Dhawan

Verstuyf

et al. 2016

Physiological Reviews

1,473

1,234

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, [1,25(OH) 2 D 3 ] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH) 2 D 3 action involves the direct binding of the 1,25(OH) 2 D 3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH) 2 D 3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH) 2 D 3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

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Effect of age on the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 by kidney of rat.

Cited by 109 publications

References 21 publications

Age-Related Changes in the 25-Hydroxyvitamin D Versus Parathyroid Hormone Relationship Suggest a Different Reason Why Older Adults Require More Vitamin D

Age-Related Changes in the 25-Hydroxyvitamin D Versus Parathyroid Hormone Relationship Suggest a Different Reason Why Older Adults Require More Vitamin D

Media Calcium Attenuates Mitochondrial 1,25(OH)2D Production in Phosphorus or Vitamin D-Deprived Rats

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

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