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M K Drezner

Publications and source records attributed to M K Drezner.

At least 55 records · Page 3Linked to original sources
PubMed1992

Multilocus mapping of the X-linked hypophosphatemic rickets gene.

X-linked hypophosphatemic rickets (HYP), the most common form of familial hypophosphatemic (vitamin D-resistant) rickets, is an X-linked dominant disorder characterized by decreased renal tubular phosphate reabsorption and consequent hypophosphatemia. Despite the application of a wide variety of biochemical and cell biology techniques, controversy exists regarding whether a primary renal abnormality underlies the abnormal phosphate transport or if this defect is secondary to the effects of a hormonal/metabolic factor. Thus localization of the HYP gene and its ultimate cloning may be necessary to elucidate the pathophysiology of the disorder. In order to map the human HYP gene we investigated several new polymorphic probes for linkage to HYP and constructed a map of markers around the gene. The database used to ascertain linkage and perform mapping included 5 large HYP kindreds, 40 Centre d'Etudie Polymorphisms Humain reference pedigrees, and 19 kindreds which had been obtained for other disease linkage studies. Two point LOD scores (odds of linkage, log10) indicate that the probes DXS365, DXS257, DXS451, and DXS41 are tightly linked to the HYP locus. Indeed, there were no cross-overs between DXS365 and HYP with a peak LOD score of 13.98 [recombination fraction (theta) = 0.00]. Moreover, multipoint analysis reveals a probable locus order of: Xtel-DXS315-DXS43-DXS257-HYP-DXS41-DXS4 51-Xcen. The likelihood of HYP occurring between DXS257 and DXS41 is 407:1 over the next most likely position. DXS365 is located between DXS41 and DXS43 but could not be located with respect to HYP and DXS257. Regardless, we have located the HYP gene between the flanking markers DXS257 (telomeric) and DXS41 (centromeric) which are 3.5 centiMorgans apart. Thus, the results of this study will facilitate attempts to further localize and eventually clone the gene.

Alleles↗
PubMed1992

Normal calcitonin stimulation of serum calcitriol in patients with X-linked hypophosphatemic rickets.

Patients with X-linked hypophosphatemic rickets (XLH) have normal or low calcitriol concentrations despite manifesting hypophosphatemia, a known stimulus of 25-hydroxyvitamin D-1 alpha-hydroxylase activity. In accord, administration of pharmacological doses of PTH results in a markedly blunted stimulation of calcitriol levels. In the murine homolog of the human disorder, the Hyp mouse, regulation of 25-hydroxyvitamin D-1 alpha-hydroxylase activity is defective in response to hypophosphatemia and PTH administration, but not in response to calcitonin administration. In the current study we administered calcitonin to controls and patients with XLH to test the hypothesis that calcitonin-stimulatable 25-hydroxyvitamin D-1 alpha-hydroxylase activity is normal in patients with XLH. We found that calcitriol concentrations increased in both groups to a similar degree (78.5 +/- 20.9 pmol/L in patients and 49.9 +/- 19.7 pmol/L in controls) and with a similar time course. Our results indicate that the complex and incomplete defect in the regulation of 25-hydroxyvitamin D-1 alpha-hydroxylase observed in Hyp mice also exists in humans.

Adult↗
PubMed1991

X-linked hypophosphatemic rickets without "rickets".

Wrist and knee radiographs from children with X-linked hypophosphatemic rickets were analyzed and compared with those from normal children and children with established rickets to assess whether radiographically apparent rickets is a consistent abnormality in X-linked hypophosphatemia. The absence or presence of rickets was correctly identified in 94.8% of wrist and knee films from normal and positive controls. In contrast, patients with X-linked hypophosphatemia exhibited rachitic abnormalities in only 5 of 11 wrist and 13 of 15 knee radiographs. As a result, 4 patients within this study group had rickets at the knee and not at the wrist, whereas 5 displayed classic defects at both sites. Perhaps more important, 2 patients, aged 3.8 and 5.2 years, displayed no evidence of rickets in either wrist or knee films, although relatives exhibited demonstrable rachitic abnormalities. Our data indicate that radiographically detectable rickets is a variable abnormality of X-linked hypophosphatemia and does not provide an unambiguous index for the diagnosis of this disease.

Adolescent↗
PubMed1991

Osteoporosis in late life: does health locus of control affect psychosocial adaptation?

Osteoporosis, a metabolic bone disease most prevalent in older adults, is a major public health problem. Although management of osteoporosis through diet, exercise, and medication has improved, little is known about the psychosocial consequences of this disabling disease. In an attempt to identify patient characteristics that would provide physicians with insight into appropriate management styles for older osteoporotics, we assessed 103 patients with osteoporosis for their health locus of control (HLOC) orientation. We examined the relationship between HLOC and patient outcomes after participation in the Duke University Preventive and Therapeutic Program for Osteoporosis (DUPATPO) to determine whether HLOC was associated with functioning after program participation. More specifically, we asked whether internal or external HLOC was associated with decreases in depression, psychiatric symptoms, and stress symptoms, or with increases in self-esteem, exercise, and disease knowledge. We have shown in our earlier work (Gold et al, J Am Geriatr Soc 1989; 37:417) that program participation is associated with improved functioning in older adults. We now asked whether knowledge of a patient's HLOC would help predict these improvements. A comparison group (ie, older osteoporotics who did not participate in DUPATPO) was also assessed for HLOC to examine the possible association between HLOC and health behaviors regardless of the DUPATPO intervention. Our findings indicate that HLOC provided little useful information regarding patient outcomes. Although improvements were seen in the mental health of program participants, no association between these improvements and HLOC could be found.

Adaptation, Psychological↗
PubMed1991

Variable phosphate-mediated regulation of vitamin D metabolism in the murine hypophosphatemic rachitic/osteomalacic disorders.

The familial hypophosphatemic (vitamin D-resistant) disorders are a variety of genetic and acquired syndromes that exhibit unexpected biochemical heterogeneity, manifest as variably abnormal or apparently normal regulation of 1,25-dihydroxyvitamin D [1,25-(OH)2D] production. Recently, we observed that Hyp and Gy mice, murine homologs of X-linked hypophosphatemic rickets, exhibit similarly disparate regulation of vitamin D metabolism. While Gy mice under basal conditions maintain an appropriate elevation (relative to hypophosphatemia) of renal 25-hydroxyvitamin D (25OHD)-1 alpha-hydroxylase, Hyp mice manifest only normal, not increased, enzyme activity. Whether such diversity results from maintenance of phosphate (P)-regulated 1,25-(OH)2D production in Gy mice and loss of this function in Hyp mice or from other variations remains unknown. Therefore, we examined the integrity of P-regulated enzyme activity in the Gy and Hyp mice by testing the effects of enzyme inhibition and alteration of the serum phosphorus concentration on 1,25-(OH)2D production. Initially, we discovered that inhibition of renal 25OHD-1 alpha-hydroxylase suppressed enzyme function in Hyp mice, but did not prevent expression of P-mediated activity in Gy mice. In this regard, while administration of a high calcium diet or 1,25-(OH)2D (0.4 ng/h, sc, for 48 h) resulted in a comparable inhibition of enzyme activity in Hyp (5.9 +/- 0.5 vs. 2.8 +/- 0.7 fmol/mg.min) and normal mice (4.4 +/- 0.6 vs. 2.0 +/- 0.2 fmol/mg.min), similar treatment did not effect complete inhibition of 25OHD-1 alpha-hydroxylase in Gy (10.3 +/- 0.6 vs. 4.9 +/- 0.3 fmol/mg.min) or P-depleted mice (10.2 +/- 0.5 vs. 5.1 +/- 0.4 fmol/mg.min). In accord with the apparent persistence of P-mediated stimulation of enzyme function in Gy mice, dietary P repletion in this mutant resulted in a serum phosphorus concentration similar to that of normal mice and decreased enzyme activity (4.0 +/- 0.8 fmol/mg.min) to a level no different from that expressed in controls (3.4 +/- 0.3 fmol/mg.min). However, in the absence of apparent P-mediated stimulation of enzyme activity, identical treatment of Hyp mice increased the serum phosphorus level comparably, but paradoxically enhanced 25OHD-1 alpha-hydroxylase (3.1 +/- 0.4 vs. 11.7 +/- 2.0 fmol/mg.min). Collectively, these data indicate that enhanced renal 25OHD-1 alpha-hydroxylase expressed in Gy mice and probably in related human diseases results from normally maintained P regulation of enzyme activity, an action absent or mutated in the genetically distinct Hyp mouse.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1991

Cyclosporin-A increases synthesis of 1,25-dihydroxyvitamin D3 in the rat and mouse.

We have previously observed elevated serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D] levels in male rats treated with oral cyclosporin-A (CsA). This elevation was independent of changes in PTH, ionized calcium, or phosphate. This paper investigates the potential sources and mechanisms for this increase in both rats and mice. Kidney homogenates from rats treated for 14 days with (15 mg/kg) had a significant increase in 25-hydroxyvitamin D (25OHD)-24-hydroxylase (24-hydroxylase) activity (149 +/- 20 vs. 89 +/- 16 fmol/mg.min; P less than 0.05), but nonsignificant increases in 25OHD-1 alpha-hydroxylase (1 alpha-hydroxylase) activity compared to controls. Kidney homogenates from C57b16J mice after the administration of 30-50 mg/kg CsA for 3 days revealed a linear dose-related increase in renal 1 alpha-hydroxylase (r = 0.96; P less than 0.05), which became significant with doses of 30 mg/kg CsA or more (P less than 0.05). To investigate the source of this 1,25-(OH)2D production, serum 1,25-(OH)2D was measured before and 48 h after bilateral nephrectomy in rats receiving CsA for 16 days. The percent decrease in serum 1,25-(OH)2D values was not significantly different in CsA-treated and untreated rats (33.9 +/- 4.9% vs. 47.5 +/- 4.9%), indicating little or no contribution from nonrenal sources. Studies of MCRs and production rates (PRs) revealed that the elevated 1,25-(OH)2D values were due to enhanced production and not altered clearance (PR, 12.4 +/- 1.2 vs. 19.1 +/- 1.9 fmol/mg.min; P less than 0.01). CsA increases 1 alpha-hydroxylase activity and produces significant elevations in serum 1,25-(OH)2D levels in both rats and mice. This increase may have an impact on bone mineral metabolism and immune modulation in postorgan transplantation patients.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1991

Aluminum-induced mitogenesis in MC3T3-E1 osteoblasts: potential mechanism underlying neoosteogenesis.

We recently reported that aluminum administration to beagles stimulates uncoupled bone formation in the marrow cavity which increases trabecular bone volume and generates new osseous networks within the axial skeleton. To investigate whether this osteogenic process results from direct stimulation of bone cell replication, we examined the mitogenic effects of aluminum on undifferentiated osteoblasts derived from the MC3T3-E1 clonal cell line. Addition of AlCl3 (1-50 microM) to serum-free culture medium of quiescent osteoblasts resulted in a dose-dependent increase in [3H]thymidine incorporation into DNA and a concordant increase in cell number to 48% of the density achieved at the maximum replicative rate induced by fetal bovine serum (FBS). The time course of aluminum-induced mitogenesis was similar to that of FBS, with onset of DNA synthesis detectable by 12 h and progressive increases in replicative rates observed over a 48-h study period. Moreover, maximal stimulation of DNA synthesis by AlCl3 and that by FBS were not additive, whereas aluminum exerted additional effects on cell replication when combined with low FBS concentrations. Analysis of cell cycle kinetics indicated that aluminum, analogous to FBS, influences the osteoblast replicative activity by inducing transition from the G0 to the S phase of the cell cycle. In addition, exposure of cells to aluminum resulted in rapid accumulation of c-fos mRNA by 30 min, indicating that aluminum, like fetal bovine serum, induced expression of growth-regulating genes. Deferoxamine mesylate, a chelator of aluminum, blocked the replicative actions of aluminum in a dose-dependent fashion. In contrast, pertussis toxin, a specific inhibitor of certain G-proteins, had no effect on the mitogenic effects of aluminum, indicating that aluminum-induced mitogenesis occurs by a pertussis toxin-insensitive pathway. Though the particular cellular pathway remains to be defined, these data provide initial evidence that aluminum-induced neoosteogenesis may depend upon direct stimulation of osteoblast replication.

Aluminum↗
PubMed1990

Aluminum-induced neo-osteogenesis: a generalized process affecting trabecular networking in the axial skeleton.

To determine if aluminum-induced neo-osteogenesis occurs in the axial skeleton, we compared spinal bone density and vertebral histology of beagles treated with aluminum for 8 and 16 weeks to that of untreated normals. Administration of aluminum (1.25 mg/kg) did not alter serum calcium, phosphorus, or creatinine but did result in a significant elevation of vertebral bone density, measured by quantitative computed tomography, after both 8 (286.7 +/- 12.4 mg/ml) and 16 (361.7 +/- 46.5 mg/ml) weeks of treatment compared with controls (212.2 +/- 4.5 mg/ml). In accord with the increased bone density, biopsies from the spine displayed evidence of neo-osteogenesis, including the presence of woven bone, both mineralized and unmineralized, within the marrow space. The genesis of such woven bone units resulted after 16 weeks in a significant increase in trabecular bone volume, woven and lamellar (51.2 +/- 4.4 versus 32.4 +/- 1.2%; p less than 0.05), woven bone volume (9.1 +/- 3.6 versus 0 +/- 0%; p less than 0.05), and trabecular number (4.5 +/- 0.3 versus 3.5 +/- 0.2 per mm; p less than 0.05). In addition, scanning electron microscopic evaluation of the bone biopsies confirmed the existence of new trabecular plates that provided interconnections between existent units. These observations illustrate that aluminum-induced neo-osteogenesis positively influences trabecular networking in the axial skeleton. Such enhancement of bone histogenesis contrasts with the effects of other pharmacologic agents that solely alter the thickness of existing trabecular plates or rods within the vertebral spongiosa.

Aluminum↗
PubMed1990

Role of calcitriol in prevention of osteoporosis: Part I.

Prevention of postmenopausal osteoporosis is an alternative to the currently problematic goal of reversing the trabecular plate thinning and perforation that constitute the major pathologic defects in patients with established osteoporosis. 1,25(OH)2D3 (calcitriol) has been suggested as a drug that may decrease bone resorption sufficiently to preserve trabecular structure in perimenopausal women. In the present study, we compared the effects of calcitriol and an investigational analog, 1,25,26-(OH)3delta22-D3 (Ro-23-8525), to those of an inert vehicle in maintaining the bone mass of oophorectomized adult beagles. In these studies, we used dual-energy radiography to serially quantitate the bone density of control and treated animals. Treatment for 1 year with either agent resulted in no evidence of hypercalcemia or decreased renal function. Moreover, calcitriol and Ro-23-8525 effectively abolished the loss of bone mass observed in untreated oophorectomized controls. Indeed, treated animals displayed variations in bone density similar to that observed in sham-operated untreated animals. These data suggest that calcitriol and Ro-23-8525 may be potentially effective agents for prophylaxis of postmenopausal osteoporosis.

Animals↗
PubMed1990

The human glycine receptor: a new probe that is linked to the X-linked hypophosphatemic rickets gene.

We undertook linkage analysis in four large North Carolina kindreds with X-linked hypophosphatemic rickets (HYP) using a newly defined polymorphic probe, derived from the 5' untranslated portion of the human glycine receptor (GLR). Two-point linkage analysis established linkage between GLR and HYP [Z(theta) = 7.91 at theta = 0.07] and confirmed linkage between HYP and DXS41 [Z(theta) = 8.31 at theta = 0.06] and DXS43 [Z(theta) = 5.94 at theta = 0.05]. Additionally, we found GLR tightly linked to DXS43 [Z(theta) = 5.40 at theta = 0.0]. Multipoint analysis indicated that GLR is on the telomeric side of HYP with a map order of Xpcen-DXS41-HYP-(GLR/DSX43).

Female↗
PubMed1990

Normal regulation of calcitriol production in Gy mice. Evidence for biochemical heterogeneity in the X-linked hypophosphatemic diseases.

Phenotypic heterogeneity in X-linked hypophosphatemic rickets (XLH) is ascribed to variable penetrance of the genetic abnormality. However, studies of hypophosphatemic (Hyp) and gyrorotary (Gy) mice indicate that mutations at different loci along the X chromosome may underlie the genetically transmitted hypophosphatemic disorders. Thus, genetic heterogeneity may be a determinant of the phenotypic variability in XLH. To determine if such variance includes biochemical diversity, we examined whether Gy mice, similar to Hyp mice, exhibit abnormal regulation of renal 25-hydroxyvitamin D (25[OH]D)-1 alpha-hydroxylase. Serum phosphorus in Gy (4.7 +/- 0.3 mg/dl) and phosphate (P)-depleted mice (4.9 +/- 0.4) was significantly less than normal (8.4 +/- 0.5). Consistent with P depletion, the Gy mice exhibited enhanced renal 25(OH)D-1 alpha-hydroxylase activity (9.3 +/- 0.6 fmol/mg kidney per min), similar to that of P-depleted normals (9.1 +/- 1.5), but significantly greater than that of controls (3.1 +/- 0.3). Such normal enzyme responsiveness was confirmed upon PTH stimulation (1 IU/h s.c.), which revealed that Gy mice increased renal 1-hydroxylase (59 +/- 7.7) similarly to normals (65 +/- 7.7) and P-depleted animals (58.4 +/- 7.8). Calcitonin administration also enhanced enzyme function comparably in the animal models. Evidence confirming normally responsive calcitriol production in untreated Gy mice included increased serum 1,25-dihydroxyvitamin D levels, gastrointestinal calcium absorption, and urinary calcium. The normally regulated vitamin D metabolism in Gy mice indicates that biochemically diverse disease may result from mutations in the gene family regulating renal P transport and underlying X-linked hypophosphatemia. We suspect such heterogeneity is due to altered P transport at variable segments of the proximal convoluted tubule.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1990

Abnormal parathyroid hormone-related peptide stimulation of renal 25-hydroxyvitamin D-1-hydroxylase in Hyp mice: evidence for a generalized defect of enzyme activity in the proximal convoluted tubule.

Previous investigations have established that hypophosphatemic (Hyp) mice exhibit diminished PTH/cAMP stimulation of 25-hydroxyvitamin D (25[OH]D)-1-hydroxylase activity in the renal proximal convoluted tubule. Whether similar muted enzyme responsiveness occurs secondary to provocation by other hormones/metabolic factors that operate by a different mechanism in the same cell system, however, remains unknown. In order to investigate this possibility, we compared renal 25(OH)D-1-hydroxylase activity of normal and Hyp mice upon stimulation with PTH-related peptide (PTHrP), a factor which may affect enzyme function in the PCT by a PTH-independent mechanism. Administration of 1-34 PTHrP, 3.0 micrograms/day sc, increased enzyme activity in normal mice (4.9 + 0.63 vs. 50.3 +/- 6.2 fmol/mg kidney.min) to a level significantly greater than that achieved in the Hyp mice (6.9 + 0.86 vs. 14.5 +/- 0.91 fmol/mg kidney.min). Moreover, similar to our observations after PTH stimulation, abnormal PTHrP effects did not result from an altered time course of enzyme activation or a shift in the dose response. Thus, the 25(OH)D-1-hydroxylase activity increased linearly to a maximum at 24 h in both animal models with a slope greater in normals than in mutants (P less than 0.05). Further, administration of PTHrP in graded amounts (0-9.0 micrograms/day) elicited a curvilinear response in normals and Hyp mice, but the mutants exhibited significantly less function (54 +/- 8.6%) at all doses tested. Additional studies revealed that the muted effects of PTHrP occurred via a PTH-independent mechanism. In this regard, we observed that simultaneous infusion of maximally effective doses of PTH and PTHrP in normal and Hyp mice resulted in an additive increment of 25(OH)D-1-hydroxylase activity. This observation that PTH and PTHrP influence renal 25(OH)D-1-hydroxylase by apparently different mechanisms indicates that the muted effects of these agents on enzyme activity in the Hyp-mouse results from a generalized defect in the proximal convoluted tubule.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1989

Treatment of osteoporosis. The psychological impact of a medical education program on older patients.

Participants in a therapeutic program for osteoporosis were studied to determine if program participation improved psychological outcomes. The 4-day program included intensive education about the disease and its prognosis, physical therapy education, nutritional counseling, and medical evaluation and treatment. All therapeutic patients enrolled in the program over a one-year period (N = 38) were interviewed individually pre- and post-participation. Knowledge of osteoporosis, level of social support, coping styles, and perceptions of the impact of pain and chronicity were assessed. Patients reported improved future outlook despite continued concern about pain and chronicity. Mention of depression was reduced, and knowledge of osteoporosis increased significantly. In addition, there were meaningful changes in patients' understanding of disease management. These included knowing when to make specific changes and avoid harmful actions. The findings suggest that an educational program can have a positive impact on patients' coping. Educational efforts may be an important component in the management of chronic disease.

Adaptation, Psychological↗
PubMed1989

Aluminum-induced de novo bone formation in the beagle. A parathyroid hormone-dependent event.

To examine the influence of osteoblast function on aluminum-induced neo-osteogenesis in the mammalian species, we compared the effects of aluminum in sham-operated and thyroparathyroidectomized (TPTX) beagles. TPTX dogs received sufficient calcium carbonate and calcitriol to maintain normal plasma calcium and calcitriol levels, but developed evidence of decreased osteoblast recruitment and activity, including diminished osteoid-covered trabecular bone surface (3.22 +/- 0.21 vs. 10.95 +/- 1.30%) and a decreased osteoblast number (27.8 +/- 8.1 vs. 139.0 +/- 26.0/mm). Administration of aluminum (1.25 mg/kg i.v., three times/wk) increased the serum aluminum levels in both sham (1,087.0 +/- 276.0 vs. 2.7 +/- 0.8 micrograms/liter) and TPTX animals (2,786.0 +/- 569.0 vs. 3.6 +/- 0.8 micrograms/liter) above normal but did not alter the plasma calcium, creatinine, or PTH from control levels in either sham or TPTX dogs. After 8 wk of therapy, however, bone biopsies from sham-operated beagles displayed evidence of neo-osteogenesis including an increased bone volume (47.0 +/- 1.0 vs. 30.4 +/- 0.9%) and trabecular number (4.1 +/- 0.2 vs. 3.2 +/- 0.2/mm). Much of the enhanced volume resulted from deposition of poorly mineralized woven bone (9.9 +/- 2.7%). In contrast, biopsies from aluminum-treated TPTX animals exhibited significantly less evidence of ectopic bone formation. In this regard, bone (35.5 +/- 1.7%) and woven tissue volume (1.4 +/- 0.8%) as well as trabecular number (3.3 +/- 0.1/mm) were significantly less than those of the aluminum-treated controls. These observations illustrate that aluminum reproducibly stimulates neo-osteogenesis and induces a positive bone balance. However, this effect apparently depends on the availability of a functional osteoblast pool which, if depleted by TPTX, limits the expression of aluminum-induced new bone formation.

Aluminum↗
PubMed1989

Abnormal adenosine 3'.5'-monophosphate stimulation of renal 1,25-dihydroxyvitamin D production in hyp mice: evidence that 25-hydroxyvitamin D-1 alpha-hydroxylase dysfunction results from aberrant intracellular function.

Previously we have established that abnormal regulation of renal 25-hydroxyvitamin D (25OHD)-1 alpha-hydroxylase in Hyp mice involves the PTH-adenylate cyclase component of enzyme activation. However, it remains unknown if the muted effects of PTH result from 1) abnormal second messenger production or 2) an intracellular defect limiting enzyme activation. To distinguish between these possibilities, we compared cAMP stimulation of renal 25OHD-1 alpha-hydroxylase in normal, phosphate-depleted normal, and Hyp mice. Administration of N6-monobutyryl cAMP iv (200 mg/kg/day) increased enzyme activity in normal (4.1 +/- 1.7 vs. 40.7 +/- 7.0 fmol/mg kidney.min) and phosphate-depleted mice (13.3 +/- 1.8 vs. 78.2 +/- 10.4) to a level significantly greater than that achieved in Hyp mice (7.4 +/- 1.1 vs. 22.7 +/- 3.6). Moreover, similar to our observations after PTH stimulation, the apparent abnormal cAMP effect did not result from an altered time course of enzyme activation or a rightward shift in the dose response. Collectively, these data indicate that abnormal regulation of 1,25-dihydroxyvitamin D production in Hyp mice results from aberrant intracellular regulation of 25OHD-1 alpha-hydroxylase, a defect probably related to deranged phosphate transport in the renal tubule.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1989

Regulation of renal 25-hydroxyvitamin D-1-hydroxylase activity in the mouse after uninephrectomy.

Although renal hypertrophy occurs rapidly after uninephrectomy, restoring the majority of renal excretory function, it remains unknown whether similar compensatory mechanisms maintain 1,25-dihydroxyvitamin D production (and calcium homeostasis). To address this issue we compared plasma calcitriol levels and renal 25-hydroxyvitamin D (25OHD)-1-alpha-hydroxylase activity (in remnant kidneys) of mice at various times after uninephrectomy to similar observations obtained in sham-operated age- and sex-matched controls. At all times postoperatively, the uninephrectomized mice sustained plasma 1,25-dihydroxyvitamin D levels no different from those of shams. Maintenance of calcitriol production occurred secondary to a significant increment of renal 25OHD-1 alpha-hydroxylase activity (per mg DNA) 1-3 days after surgery when renal mass/function remained markedly depressed. In contrast, 10 and 21 days postoperatively, when hypertrophy was complete, enhanced enzyme function was no longer apparent. Throughout this period a significant inverse linear correlation existed between renal 25OHD-1 alpha-hydroxylase and the renal mass as well as glomerular filtration rate and renal blood flow. The variance in enzyme activity resulted in maintenance of a stable renal 25OHD-1 alpha-hydroxylase (per animal or total kidney mass) at all times investigated postuninephrectomy. Such compensatory regulation of vitamin D metabolism after unilateral kidney extirpation may be an important factor contributing to the low morbidity/mortality in the renal donor.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗