Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A recent study by Steiner et al. (Biochem Pharmacol 51: 253-258, 1996) demonstrated a decreased calbindin D28K expression in the kidneys of cyclosporin A (CsA)-treated rats. To evaluate the association of renal calcium handling with calbindin D28K expression in CsA-treated rats, two separate experiments (vehicle [VH] versus CsA groups, 1,25-dihydroxyvitamin D3 [VitD] versus VitD + CsA groups) were done simultaneously. CsA (25 mg/kg per d, subcutaneously) and VitD (0.5 microg/kg per d, subcutaneously) were given for 7 d. The CsA group showed decreased serum calcium, increased urine calcium excretion, and decreased calbindin D28K protein level and immunoreactivity compared with the VH group. The VitD + CsA treatment decreased serum calcium, increased urine calcium excretion, and decreased calbindin D28K protein level and immunoreactivity compared with the VitD alone. CsA treatment did not affect the serum parathyroid hormone and VitD levels. This study demonstrates an association of calbindin D28K expression with the urinary calcium excretion in CsA-treated rats, and suggests that decreased calbindin D28K expression may play a role in renal calcium wasting.
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PMID:Inhibition of calbindin D28K expression by cyclosporin A in rat kidney: the possible pathogenesis of cyclosporin A-induced hypercalciuria. 969 63

We have shown previously that chronic hyperchloremic metabolic acidosis (CMA) induces severe negative nitrogen balance and renal phosphate depletion and decreases serum insulin-like growth factor-1 (IGF-1) in association with growth hormone (GH) insensitivity in humans. The present study investigated whether acidosis-induced renal nitrogen wasting and renal phosphate depletion are mediated by GH insensitivity/low IGF-1 and thereby responsive to GH treatment. The effects of GH on acidosis-induced changes in divalent cation metabolism and acidosis-induced hypothyroidism were also investigated. CMA (delta[HCO3], -10.5 mmol/L) was induced in six healthy male subjects ingesting 4.2 mmol NH4Cl/kg body weight [BW]/d for 7 days. Recombinant human GH (0.1 U/kg BW/12 h subcutaneously) was administered for 7 days while acid feeding was continued. GH increased serum IGF-1 from 22.1 +/- 1.4 to 87 +/- 8.4 nmol/L (control level, 36.4 +/- 2.2). GH decreased urinary nitrogen excretion, resulting in a cumulative nitrogen retention of 2,404 mmol, thereby correcting the acidosis-induced cumulative increase in nitrogen excretion (2,506 mmol) despite continued acid feeding. GH attenuated the acidosis-induced hyperphosphaturia (cumulative phosphate retention, 91 mmol) and corrected the hypophosphatemia. GH did not affect acidosis-induced ionized hypercalcemia, but further exacerbated acidosis-induced hypercalciuria (cumulative loss, 27.3 mmol). GH significantly further increased serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and further decreased intact PTH (from 10 +/- 1 to 6 +/- 1 pg/mL). Acidosis also induced hypomagnesemia and hypermagnesuria (cumulative loss, 9.4 mmol, ie, renal magnesium wasting), a novel finding, which was significantly attenuated by GH (cumulative retention, 5.0 mmol). In conclusion, GH corrected acidosis-induced renal nitrogen wasting, which may be caused, at least in part, by decreased IGF-1 levels. GH further increased serum 1,25(OH)2D and the systemic calcium load, which account for the suppression of parathyroid hormone (PTH) despite renal PO4 retention and correction of hypophosphatemia. GH attenuated acidosis-induced renal magnesium wasting.
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PMID:Growth hormone corrects acidosis-induced renal nitrogen wasting and renal phosphate depletion and attenuates renal magnesium wasting in humans. 1038 Nov 52

The clinical use of aminoglycosides often leads to renal magnesium wasting and hypomagnesemia. Of the nephron segments, both the thick ascending limb of Henle's loop and the distal tubule play significant roles in renal magnesium conservation but the distal convoluted tubule exerts the final control of urinary excretion. An immortalized mouse distal convoluted tubule (MDCT) cell line has been extensively used to study the cellular mechanisms of magnesium transport in this nephron segment. Peptide hormones, such as parathyroid hormone (PTH), glucagon, calcitonin, and arginine vasopressin (AVP) stimulate Mg2+ uptake in MDCT cells that is modulated by extracellular polyvalent cations, Ca2+ and Mg2+. The present studies determined the effect of aminoglycosides on parathyroid hormone (PTH)-mediated cAMP formation and Mg2+ uptake in MDCT cells. Gentamicin, a prototypic aminoglycoside, elicited transient increases in intracellular Ca2+ from basal levels of 102 +/- 13 nM to 713 +/- 125 nM, suggesting a receptor-mediated response. In order to determine Mg2+ transport, MDCT cells were Mg(2+)-depleted by culturing in Mg(2+)-free media for 16 h and Mg2+ uptake was measured by microfluorescence after placing the depleted cells in 1.0 mM MgCl2. The mean rate of Mg2+ uptake, d([Mg2+]i)/dt, was 138 +/- 24 nM/s in control MDCT cells. Gentamicin (50 microM) did not affect basal Mg2+ uptake (105 +/- 29 nM/s), but inhibited PTH stimulated Mg2+ entry, decreasing it from 257 +/- 36 nM/s to 108 +/- 42 nM/s. This was associated with diminished PTH-stimulated cAMP formation, from 80 +/- 2.5 to 23 +/- 1 pmol/mg protein x 5 min. Other aminoglycosides such as tobramycin, streptomycin, and neomycin also inhibited PTH-stimulated Mg2+ entry and cAMP formation. As these antibiotics are positively charged, the data suggest that aminoglycosides act through an extracellular polyvalent cation-sensing receptor present in distal convoluted tubule cells. We infer from these studies that aminoglycosides inhibit hormone-stimulated Mg2+ absorption in the distal convoluted tubule that may contribute to the renal magnesium wasting frequently observed with the clinical use of these antibiotics.
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PMID:Aminoglycosides inhibit hormone-stimulated Mg2+ uptake in mouse distal convoluted tubule cells. 1095 59

Oncogenic osteomalacia (OOM) is characterized by renal phosphate wasting and abnormal metabolism of vitamin D, somewhat similar to the phenotype of X-linked hypophosphatemic rickets (HYP). DNA from OOM tumor cells was analyzed for mutations in the PHEX gene, which is mutated in HYP. Screening for mutations by single-strand conformation polymorphism analysis and subsequent sequencing of all the exons revealed no mutations. Conditioned media from long-term cultures of OOM tumor cells were used to further characterize the physical properties of the phosphate-regulating factor and its mechanism of action. Inhibition of OK 3B2 cell renal phosphate transport by conditioned media was dose-dependent and maximal after 20 h. This time course differed from that of parathyroid hormone (PTH). The bioactivity was stable to mild acid and alkali treatment and freeze drying and was retained in the aqueous phase following organic solvent extraction. The activity was not suppressed by heat or by treatment with trypsin but was suppressed by the protease papain and had an apparent molecular weight of < 5000. No change was detected in the expression of type II sodium/phosphate cotransporter (NaPi) mRNA in OK 3B2 cells in response to conditioned media, unlike the reduction seen in Hyp mice. In the presence of colchicine or cytochalasin D, the inhibitory response to conditioned media was reduced, similar to the effect of these agents on the response to PTH. Cycloheximide also suppressed the inhibitory response of conditioned media, but not the response to PTH. These studies indicate that mutations in the PHEX gene are unlikely to be responsible for OOM and suggest that the tumor-derived factor that inhibits phosphate uptake is a small protein that does not downregulate type II NaPi mRNA, and requires an intact cytoskeleton and protein synthesis for activity.
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PMID:Phosphate wasting in oncogenic osteomalacia: PHEX is normal and the tumor-derived factor has unique properties. 1133 25

In oncogenic osteomalacia (OOM), a tumor produces an unknown substance that inhibits phosphate reabsorption in the proximal tubules. This causes urinary phosphate wasting and, as a consequence, hypophosphatemic osteomalacia. To characterize this poorly understood biological tumor activity we generated aqueous extracts from several OOM tumors. Extracts from three of four tumors inhibited, dose- and time-dependently, (32)P-orthophosphate uptake by opossum kidney (OK) cells; maximum inhibition was about 45% of untreated control. Further characterization revealed that the factor is resistant to heat and several proteases, and that it has a low molecular weight. The tumor extracts also stimulated cAMP accumulation in OK cells, but not in osteoblastic ROS 17/2.8 and UMR106 cells, or in LLC-PK1 kidney cells expressing the parathyroid hormone (PTH)/PTH-related peptide receptor or the PTH-2 receptor. HPLC separation of low molecular weight fractions of the tumor extracts revealed that the flow-through of all three positive tumor extracts inhibited (32)P uptake and stimulated cAMP accumulation in OK cells. Additionally, a second peak with inhibitory activity on phosphate transport, but without cAMP stimulatory activity, was identified in the most potent tumor extract. We have concluded that several low molecular weight molecules with the ability to inhibit phosphate transport in OK cells can be found in extracts from OOM tumors. It remains uncertain, however, whether these are related to the long-sought phosphaturic factor responsible for the phosphate wasting seen in OOM patients.
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PMID:Extracts from tumors causing oncogenic osteomalacia inhibit phosphate uptake in opossum kidney cells. 1137 32

Metabolic acidosis is an important acid-base disturbance in humans. It is characterised by a primary decrease in body bicarbonate stores and is known to induce multiple endocrine and metabolic alterations. Metabolic acidosis induces nitrogen wasting and, in humans, depresses protein metabolism. The acidosis-induced alterations in various endocrine systems include decreases in IGF-1 levels due to peripheral growth hormone insensitivity, a mild form of primary hypothyroidism and hyperglucocorticoidism. Metabolic acidosis induces a negative calcium balance (resorption from bone) with hypercalciuria and a propensity to develop kidney stones. Metabolic acidosis also results in hypophosphataemia due to renal phosphate wasting. Negative calcium balance and phosphate depletion combine to induce a metabolic bone disease that exhibits features of both osteoporosis and osteomalacia. In humans at least, 1,25-(OH)2 vitamin D levels increase, probably through phosphate depletion-induced stimulation of 1-alpha hydroxylase. The production rate of 1,25-(OH)2 vitamin D is thus stimulated, and parathyroid hormone decreases secondarily. There is experimental evidence to support the notion that even mild degrees of acidosis, such as that occurring by ingestion of a high animal protein diet, induces some of these metabolic and endocrine effects. The possible role of diet-induced acid loads in nephrolithiasis, age-related loss of lean body mass and osteoporosis is discussed.
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PMID:Metabolic and endocrine effects of metabolic acidosis in humans. 1141 68

Over the past decade, three classes of Na/Pi cotransporters have been identified in mammalian kidney. The type IIa Na/Pi cotransporter, Npt2, is the most abundant and is expressed in the brush-border membrane of renal proximal tubular cells where the bulk of filtered inorganic phosphate (Pi) is reabsorbed. Disruption of the Npt2 gene in mice underscored the importance of Npt2 in the overall maintenance of Pi homeostasis and demonstrated that Npt2 is the target for regulation of proximal tubular Pi reabsorption by parathyroid hormone and dietary Pi. The regulation is post-transcriptional and largely occurs by brush-border membrane retrieval and insertion of Npt2 protein. Of great interest is the recent identification of novel Pi regulating genes, PHEX and FGF23, that play a role in the pathophysiology of inherited (X-linked hypophosphatemia and autosomal dominant hypophosphatemic rickets) and acquired (oncogenic hypophosphatemic rickets) disorders characterized by renal Pi wasting and associated skeletal abnormalities. Studies are currently underway to elucidate the molecular basis for impaired renal Pi reabsorption in these disorders and to determine the precise physiological role of PHEX and FGF-23 in the regulation of Pi homeostasis.
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PMID:Novel phosphate-regulating genes in the pathogenesis of renal phosphate wasting disorders. 1211 Dec 39

Our understanding of disorders that present with hypocalcaemia has advanced rapidly in the past decade. The molecular basis of many of these disorders and conditions associated with phosphate wasting has now been established. While many children will need specialist involvement, they often will present to general paediatricians, and appropriate investigations prior to intervention will enable early diagnosis. Not all children with hypocalcaemia and low or low normal parathyroid hormone levels have isolated hypoparathyroidism, and clinicians need to be aware of the potential for misdiagnosis. Outpatient departments and paediatric wards should have a readily accessible and comprehensive list of bloods that need to be taken when a child presents with hypocalcaemia or rickets.
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PMID:The investigation of hypocalcaemia and rickets. 1271 11

A 5-year-old girl presented with short stature. She was found to have rickets due to renal phosphate wasting and nephrocalcinosis. Serum parathyroid hormone was suppressed, 25-OH vitamin D was within the normal range, and 1,25-(OH)(2 )vitamin D was elevated. In addition, she had hypercalciuria, proteinuria, which was partially tubular in origin, and a reduced glomerular filtration rate of 58 ml/min per 1.73 m(2). Treatment with phosphate supplements resulted in healing of the rickets and normalization of the serum 1,25-(OH)(2 )vitamin D level. This patient is an example of hypercalciuric rickets, most likely due to an inherited disorder of phosphate metabolism. Hypercalciuric rickets can be inherited as an autosomal recessive as well as autosomal dominant trait.
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PMID:A girl with rickets and nephrocalcinosis. 1464 29

Mutations in the PHEX gene are responsible for X-linked hypophosphatemia, a renal phosphate-wasting disorder associated with defective skeletal mineralization. PHEX is predominantly expressed in bones and teeth and in the parathyroid gland of patients with chronic renal failure and tertiary hyperparathyroidism. The purpose of the present study was to examine the effects of renal insufficiency and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the regulation of PHEX expression in rat tibia and parathyroid gland. In rats fed a high-phosphate (Pi) diet, nephrectomy elicited a significant increase in the serum parathyroid hormone (PTH) concentration that was associated with a significant increase in the abundance of PHEX mRNA and protein in the tibia and a significant increase in PHEX mRNA in the parathyroid gland. In contrast, 1,25(OH)2D3 administration to intact rats fed a control diet elicited a significant decrease in the serum PTH concentration that was accompanied by a significant decrease in PHEX mRNA and protein abundance in the tibia and a significant decrease in PHEX mRNA in the parathyroid gland. In addition, the increases in serum PTH levels and PHEX mRNA in the tibia and parathyroid gland in nephrectomized rats fed a high-Pi diet were blunted by 1,25(OH)2D3. Serum PTH concentration was positively and significantly correlated with tibial PHEX mRNA and protein abundance. In summary, we demonstrate that PHEX expression in the tibia and parathyroid gland is increased by chronic renal insufficiency and decreased by 1,25(OH)2D3 administration and suggest that PTH status may play an important role in mediating these changes in PHEX expression.
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PMID:Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D3. 1469 75


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