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J Caverzasio

Publications and source records attributed to J Caverzasio.

At least 73 records · Page 4Linked to original sources
PubMed1988

Factor derived from human lung carcinoma associated with hypercalcemia mimics the effects of parathyroid hormone on phosphate transport in cultured renal epithelia.

A decrease in renal tubular reabsorption of inorganic phosphate (Pi) can be observed in hypercalcemia of malignancy. In the present study we investigated the effect of serum-free conditioned medium (CM) from cells, derived from a lung carcinoma (BEN) of a hypercalcemic patient, and of PTH on cyclic AMP (cAMP) production and sodium-dependent Pi transport (NaPiT) in epithelia of two renal cell lines. In opossum kidney cells (OK), PTH is known to enhance cAMP production and inhibit NaPiT; in contrast, in LLC-PK1 cells, PTH has no effect on NaPiT since this kidney cell line is devoid of PTH receptors. In OK cells, BEN CM induced a three- to fourfold increase of cAMP production, which was blunted by the PTH inhibitors bPTH(3-34) and bPTH(7-34). NaPiT, as assessed by measuring the initial rate of Pi uptake, was inhibited in a dose-dependent manner by BEN CM, with an effect maximal between 1h30 and 6 hr of incubation (40 +/- 4% and 47 +/- 4%, respectively), corresponding to the effect produced by 1-3 nM bPTH(1-34). The Na-dependent transport of a glucose analog was affected neither by BEN CM nor by PTH. In LLC-PK1 cells, neither BEN CM nor PTH altered cAMP production nor NaPiT after 1h30 of incubation. At 6 hr, BEN CM caused a slight decrease in NaPiT. In conclusion, these results constitute the first evidence of a direct and selective inhibition by tumor-derived factor(s) of NaPiT in cultured renal epithelia. Most of the renal NaPiT inhibitory activity produced by the lung tumor required the presence of a PTH receptor-adenylate cyclase system.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Tumoral synthetic parathyroid hormone related peptide inhibits amiloride-sensitive sodium transport in cultured renal epithelia.

The amino-terminal fragment of a tumor parathyroid hormone-related peptide (PTHrP(1-34] produced by a human squamous cell carcinoma of the lung was recently synthesized. In the present work its effect on the amiloride-sensitive sodium transport, taken as an estimate of the Na+/H+ exchanger activity of cultured opossum kidney (OK) epithelia was compared to that of synthetic bovine parathyroid hormone (bPTH(1-34]. Both PTHrP(1-34) and bPTH(1-34) inhibited the initial rate of amiloride-sensitive 22Na transport. Half maximal inhibitory activity was obtained at about 10(-11)M for both PTHrP(1-34) and bPTH(1-34). In conclusion, tumoral PTHrP(1-34) appears to be as effective as bPTH(1-34) for inhibiting the amiloride-sensitive Na transport, and presumably for decreasing the activity of the Na+/H+ exchanger present in the apical membrane of kidney epithelial cells.

Amiloride↗
PubMed1988

Characteristics of phosphate transport in osteoblastlike cells.

The characteristics of the transport of inorganic phosphate (Pi) in osteoblastic cells have been determined using the osteosarcoma cell line ROS 17/2.8. The initial rate of the Pi transfer from the extracellular into the intracellular osteoblastic compartment is mediated by a sodium-dependent process. The stoichiometric analysis of the cotransport system suggests that two sodium ions would be transferred with each Pi molecule. In the presence of sodium, the Pi transfer was saturable with increasing extracellular Pi concentration. In the absence of extracellular sodium, only a negligible amount of Pi enters the osteoblastic cells, with a kinetic compatible with a simple diffusion process. The kinetic parameters of the saturable component of the Pi transport measured at an external sodium concentration of 143 mmol/liter were Km = 448 +/- 12 mumol/liter; Vmax = 37.1 +/- 0.7 nmol/mg prot. 4 min. In the presence of 0.1 mmol/liter Pi, the half-maximal activation by sodium was obtained at 43 +/- 1.3 mmol/liter. The Pi transport rate was reduced by arsenate, by metabolic inhibitors such as FCCP and by ouabain, an inhibitor of Na-K ATPase. These results strongly suggest that the Pi transfer into osteoblastic cells is a carrier-mediated process which is driven by the transmembrane electrochemical gradient of sodium.

Animals↗
PubMed1988

Protection from progressive renal failure and hyperparathyroid bone remodeling by WR-2721.

In chronic renal failure (CRF), secondary hyperparathyroidism (sHPT) plays a major role in skeletal lesions and also probably in the deterioration of renal functions consecutive to nephrocalcinosis. In this study we tested whether WR-2721 [S-,2-(3-aminopropylamino)-ethylphosphorothioic acid], an inhibitor of parathyroid hormone (PTH) secretion, could prevent the deleterious effects of sHPT at both the bone and kidney level in an animal model of CRF. Rats were either subtotally nephrectomized (NX) or sham-operated (SHAM). They were then pairfed a high phosphorus (1.4%), middle Ca (0.6%) diet. This regimen accelerated the deterioration of renal function in NX rats which displayed signs of severe sHPT in bone (three- to fourfold increase in osteoclast number and resorption surfaces) and kidney (sixfold increase in Ca content) after four weeks. Chronic administration of WR-2721 (20 mg = 0.093 mmol/kg s.c. twice daily) during four weeks completely prevented the progressive elevation of both plasma urea and inorganic phosphate, and the fall of plasma Ca. It also prevented kidney Ca accumulation to the same extent as parathyroidectomy. However, WR-2721 given at this dose only partially prevented the histomorphometric indices of increased bone resorption and formation. This discrepant response suggests that WR-2721 could exert an additional protective effect at the kidney level that might be related to its property of acting as a free radical scavenger. In conclusion, this study suggests that WR-2721 might be a useful compound in CRF, not only because it inhibits PTH secretion, but also because it could protect against the deleterious effect of secondary hyperparathyroidism on kidney functions.

Amifostine↗
PubMed1988

Influence of calcium on phosphate transport in cultured kidney epithelium.

Renal epithelia cultured from opossum kidney (OK) cell line were exposed to high- and low-Ca media (HCaM and LCaM, respectively). Changing the extracellular Ca concentration from 2.0 mM to 0.02 mM stimulated sodium-dependent Pi transport (NaPiT) of OK epithelia. The effect was detectable after 1 h of LCaM exposure and reached a maximal value at 4 h (HCaM, 1.49 +/- 0.02; LCaM, 2.71 +/- 0.02 nmol.mg prot-1.4 min-1, P less than 0.001), this difference remaining constant up to 16 h. The Na-dependent transports of both alanine and methyl-alpha-D-glucopyranoside, a glucose analogue, were not affected by LCaM. Kinetic analysis of NaPiT revealed an increase in Vmax with no change in the apparent Km. The cellular adenosine 3',5'-cyclic monophosphate production was not affected by LCaM. In OK epithelia pretreated with either cycloheximide or actinomycin D the LCaM stimulatory effect was completely abolished. In the presence of 10(-9) to 10(-7) M bovine parathyroid hormone (1-34), the effect of LCaM on NaPiT was markedly blunted. In conclusion, this study in cultured kidney epithelia demonstrates that the renal NaPiT can be directly and selectively stimulated by lowering the extracellular Ca concentration. This effect required the de novo synthesis of proteins. The results also indicate that parathyroid hormone antagonizes the stimulatory effect of extracellular Ca on the renal transport of Pi.

Animals↗
PubMed1988

Effect of synthetic tumoral PTH-related peptide on cAMP production and Na-dependent Pi transport.

Malignant hypercalcemia can be associated with a biochemical syndrome very similar to that encountered in primary hyperparathyroidism. The putative tumoral factor responsible for this syndrome has been isolated very recently from conditioned medium of a cultured lung squamous cell carcinoma (BEN), cDNA clones characterized, and an amino-terminal fragment synthesized. We investigated and compared the effect of this synthetic amino-terminal fragment of parathyroid hormone-related peptide [PTHrP-(1-34)], to purified PTHrP-(1-141) isolated from the same lung squamous cell carcinoma, and to bovine parathyroid hormone [bPTH-(1-34)] on adenosine 3',5'-cyclic monophosphate (cAMP) production and sodium-dependent phosphate transport (NaPiT) in opossum kidney (OK) epithelial cells. PTHrP-(1-34) and bPTH-(1-34) were equipotent in eliciting a 30-fold increase of cAMP production. NaPiT, as assessed by measuring the initial rate of Pi uptake, was inhibited in a concentration-dependent manner by either synthetic peptide. Half-maximal inhibition was observed with approximately 0.03-0.1 nmol/l of either bPTH-(1-34) or PTHrP-(1-34). At 10 nmol/l, either peptide produced an inhibition of 55 +/- 4 and 53 +/- 6%, respectively. This effect was specific for Pi, since the Na-dependent transport of glucose or alanine was not altered by either peptide. In OK cells dose-dependent stimulation of cAMP production and inhibition of NaPiT were also observed with purified native PTHrP-(1-141). In LLC-PK1 cells, which are devoid of PTH receptors, none of the peptides affected NaPiT. These results demonstrate a direct and specific effect of tumoral PTHrP on cAMP production and NaPiT in cultured renal epithelial cells in a way similar to bPTH.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1987

Adaptation of phosphate transport to low phosphate diet in renal and intestinal brush border membrane vesicles: influence of sodium and pH.

The possible role of changes in the sodium (Na) affinity of the carrier for inorganic phosphate (Pi) in the adaptation of Pi transport to low Pi diet was examined in both renal and intestinal brush border membranes vesicles (BBMV) obtained from the same animal. This role was assessed by measuring the Na concentration resulting in half maximal activation of Pi transport (K0.5 Na) in renal and intestinal BBMV prepared from animals adapted to either low (LPD) or high (HPD) phosphorus diet for 7 days. The K0.5 Na was not modified by dietary Pi, in both renal and intestinal BBMV. LPD increased maximal Pi transport from 1794.8 +/- 198.0 to 2964.0 +/- 362.0 in renal and from 28.2 +/- 3.4 to 80.5 +/- 7.2 pmol/mg 10 s in intestinal BBMV. For both LPD and HPD lowering pH from 7.4 to 6 dramatically increased K0.5 Na in renal and intestinal BBMV. As compared to pH 7.4, it was enhanced by approximately 200% in both renal and intestinal membranes. This change of Na affinity with acidic pH prevented the expression of Pi transport adaptation at 100 mM Na concentration. However, at saturating Na concentrations (500 mM for renal, 300 mM for intestinal membranes), Pi transport adaptation was equally expressed at pH 6 and 7.4 in both types of membranes. Hill coefficient analysis indicates a 2:1 stoichiometry of Na to Pi in renal and intestinal membranes isolated from high or low Pi diet animals. This ratio was not modified by changes of the medium pH.

Adaptation, Physiological↗
PubMed1987

Prevention of parathyroid hormone-dependent nephrocalcinosis by chronic administration of the organic phosphorothioate WR-2721.

Pharmacological inhibition of parathyroid hormone (PTH) secretion has been the object of several experimental and clinical trials in the past. It is only recently that a drug, WR-2721 [S-,2-(3-aminopropylamino)-,ethylphosphorothioic acid], has been shown to effectively inhibit PTH secretion in euparathyroid subjects and in parathyroid cancer patients within a few hours after its administration. In the present study we tested its long term efficacy as a PTH inhibitor in a model of nephrocalcinosis resulting from secondary hyperparathyroidism. Intact and thyroparathyroidectomized (TPTX) rats were pair-fed on a low Ca (0.2%)-high phosphorus (1.6%) diet (nephrocalcinotic diet) or on a normal Ca (1.1%)-normal phosphorus (0.8%) diet for 7 days. Simultaneously, either 0.2 mmol/kg of WR-2721 or its solvent was injected subcutaneously twice daily. The intact animals on the nephrocalcinotic diet had an increased urinary cyclic AMP excretion and important renal Ca accumulation. This nephrocalcinosis was markedly reduced by WR-2721 treatment. The kidney Ca content of the WR-2721-treated rats was 58 +/- 6% lower than that of the nontreated animals. The low Ca-high phosphorus diet did not cause nephrocalcinosis in the TPTX rats. WR-2721 failed to reduce the nephrocalcinosis induced by 1,25 dihydroxyvitamin D3 intoxication in TPTX rats fed the normal Ca-normal phosphorus diet. In conclusion, the present study suggests that chronic treatment with WR-2721, a potent inhibitor of PTH secretion, may be effective for preventing the deleterious consequences of hyperparathyroidism, such as nephrocalcinosis.

Amifostine↗
PubMed1987

Interleukin-1 decreases renal sodium reabsorption: possible mechanism of endotoxin-induced natriuresis.

Administration of pyrogen or endotoxins such as Escherichia coli lipopolysaccharide can elicit a marked increase in urinary sodium excretion. This response occurs without any elevation in the filtered load of sodium and it does not appear to be prostaglandin mediated. The various effects produced by endotoxins appear to have interleukin-1 as a common mediator. In the present work, we have studied whether human recombinant interleukin-1 beta (hrIL-1) could affect the renal handling of sodium and thus, could be implicated in natriuretic response to pyrogens or endotoxins. We observed that hrIL-1 intravenously injected into conscious rats provokes a marked increase in sodium excretion. This natriuretic response was not associated with any increase in glomerular filtration rate (clearance of [3H]inulin), nor was it accompanied by significant changes in the urinary excretion of potassium, calcium, or inorganic phosphate. The only concomitant alteration was a decrease in urinary pH. Pretreatment with indomethacin abolished the effect of hrIL-1 on urinary pH but did not modify the natriuretic response. In conclusion, hrIL-1 elicits a selective decrease in tubular sodium reabsorption, which does not appear to involve a change in prostaglandin synthesis. This observation strongly suggests that interleukin-1 could be a key mediator in endotoxin-induced natriuresis.

Absorption↗
PubMed1987

Management of hypercalcemia in relation to pathophysiology.

Hypercalcemia results from an imbalance between the fluxes of calcium (Ca) entering and leaving the extracellular space. The two most important influxes are the net intestinal Ca absorption and the net skeletal Ca resorption, whereas the renal excretion represents the main route of elimination. When produced in excess, various factors, particularly calciotropic hormones and cytokines, can disturb the Ca fluxes at intestinal, skeletal and renal tubular sites. If the excessive production of these substances cannot be controlled by surgical or pharmacological means, the next most rational therapeutic strategy should be aimed at correcting those Ca fluxes which are abnormally increased. In hypercalcemia of malignancy (HM), an augmentation in net bone resorption (BR) is observed in most patients. However, a sustained stimulation in tubular Ca reabsorption (TRCa), despite correction of volume depletion by saline infusions, may not only contribute to the hypercalcemia, but in some cases it appears to be the prevailing disturbance. In these patients the effects of the antiresorbing agent clodronate (500 mg/8 h iv in one single infusion) is incomplete, despite the normalisation of BR. Thus, administration of an antiresorbing agent, such as clodronate, is the treatment of choice in HM with elevated BR and normal TRCa. It should be given with other therapeutic agents when a sustained increase in TRCa is the prevailing mechanism for hypercalcemia. In this regard, experimental studies suggest that the agent WR-2721, which specifically inhibits TRCa could be an effective drug for rapidly lowering plasma Ca in HM with high TRCa.

Amifostine↗
PubMed1986

Sodium-dependent phosphate transport inhibited by parathyroid hormone and cyclic AMP stimulation in an opossum kidney cell line.

In the present study we investigated the characteristics of the transport of inorganic phosphate (Pi) in an opossum kidney cell line endowed with parathyroid hormone (PTH) receptors. In confluent epithelial cell culture, a Na-dependent Pi transport (NaPiT) was identified. Preincubation for 1 h with bovine (b)PTH(1-34) at 10(-7) M inhibited the NaPiT from 2.76 +/- 0.11 to 1.08 +/- 0.10 nmol/mg protein X 2 min-1 (p less than 0.001). This inhibition was already expressed 5 min after exposure to 10(-7) M bPTH. It was associated with a 4-fold increase in cellular cyclic AMP. The NaPiT was significantly inhibited at 10(-9) M bPTH, a hormonal concentration which stimulated the cellular cyclic AMP by only 30%. Kinetic analysis of the NaPiT inhibition by 10(-7) M bPTH revealed a decrease in Vmax (from 4.14 +/- 0.32 to 2.41 +/- 0.14 nmol/mg protein X 2 min-1) with no change in Km (0.093 +/- 0.016 versus 0.094 +/- 0.012 mM). The effect of bPTH on NaPiT was not associated with a change in the Na-dependent glucose methylglucopyranoside transport also present in the opossum kidney cell line. The inhibitory influence of bPTH on NaPiT was not affected by blockage of new protein synthesis by cycloheximide. Stimulation of cyclic AMP production by 10(-5) M forskolin, 10 micrograms/ml cholera toxin, 10(-5) M prostaglandin E2 or addition of 10(-5) M dibutyryl cyclic AMP mimicked the PTH-induced reduction in NaPiT. In conclusion, the present study indicates that the opossum epithelial cell line is endowed with a Na-dependent Pi transport system which is selectively inhibited by PTH and agents which increase cyclic AMP production.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Normalization of hypercalcemia associated with a decrease in renal calcium reabsorption in Leydig cell tumor-bearing rats treated with WR-2721.

The Rice-500 Leydig cell tumor (LCT) in Fischer rats is a model of humoral hypercalcemia of malignancy (HHM). In this model, the elevation of plasma calcium (Ca) does not result merely from an increased bone resorption, but also from an enhanced tubular Ca reabsorption (TRCa). We investigated the hypocalcemic response to WR-2721 [S-2,2-(3-aminopropylamino)-, ethylphosphorothioic acid] in LCT-bearing Fischer rats. WR-2721 is a potent inhibitor of normal and aberrant parathyroid hormone (PTH) secretion. Moreover, it exerts a PTH-independent inhibitory effect on TRCa. In hypercalcemic LCT-bearing rats WR-2721 induced a fall in plasma Ca from 3.24 +/- 0.12 to 2.66 +/- 0.23 mmol/liter within 2 h after one single injection of 0.7 mmol/kg body wt. The decrement in plasma Ca was associated with a marked increase in urinary Ca excretion, indicating an inhibition of TRCa. The elevated urine cyclic AMP of LCT-bearing rats, however, was not altered by WR-2721 treatment. These results suggest that in this HHM model, WR-2721 can normalize calcemia through its PTH-independent inhibitory effect on TRCa. WR-2721 could therefore be an effective drug to treat human hypercalcemia of malignancy, particularly in those tumors wherein a markedly enhanced renal Ca reabsorption contributes to the elevation of the plasma Ca level.

Absorption↗
PubMed1986

Parathyroid hormone-like changes in renal calcium and phosphate reabsorption induced by Leydig cell tumor in thyroparathyroidectomized rats.

The Leydig cell tumor Rice H-500 is a model of humoral hypercalcemia of malignancy. Hypercalcemia is considered to result mainly from increased bone resorption. However, a change in renal tubular reabsorption of calcium (Ca) as a contributing factor to the hypercalcemia has not yet been recognized. The purpose of this study was to examine whether the renal handling of Ca was altered in Leydig cell tumor-bearing rats. To avoid counterregulations by Ca-regulating hormones, the effect of the Leydig cell tumor on plasma Ca and phosphate (Pi), urinary Ca and Pi excretion, as well as Ca and Pi renal tubular reabsorptive capacity was investigated in thyroparathyroidectomized rats. Clearance experiments were conducted at a time of tumor development when the glomerular filtration rate was not compromised. Under these conditions, tubular reabsorption of Ca was stimulated, and the maximal tubular reabsorption of Pi was markedly reduced (2.69 +/- 0.27 vs. 4.57 +/- 0.21 mumol/min; P less than 0.001). These changes were accompanied by increased urinary cAMP excretion (77.1 +/- 6.3 vs. 34.7 +/- 2.8 pmol/ml glomerular filtrate; P less than 0.001). These results indicate that the Leydig cell tumor produces a factor with PTH-like activity on the renal tubular reabsorption of Ca and Pi. The increased tubular reabsorption of Ca may play an important role in the pathogenesis of Leydig cell tumor-induced hypercalcemia. This animal model appears to be particularly appropriate for studying the mechanisms of certain types of humoral hypercalcemia of malignancy, as some cancer patients display a change in the renal handling of Ca similar to that observed in primary hyperparathyroidism.

Absorption↗