Biomedical subjects

J Caverzasio

Publications and source records attributed to J Caverzasio.

At least 19 recordsLinked to original sources

PubMed1992

Inhibition of bone resorption by the bisphosphonate BM 21.0955 is not associated with an alteration of the renal handling of calcium in rats infused with parathyroid hormone-related protein.

Hypercalcaemia of malignancy is determined by an increase of bone resorption and/or renal tubular reabsorption of calcium (Ca). However, this latter component has been found to vary in certain patients during therapy with bone resorption inhibitors such as bisphosphonates. We investigated the possible effects of the highly potent bisphosphonate BM 21.0955 on the renal handling of Ca in thyroparathyroidectomized rats made hypercalcaemic by the stimulation of both bone resorption and renal tubular reabsorption of Ca induced by the chronic infusion of parathyroid hormone-related protein (PTHrP). Dose-dependent inhibition of bone resorption by BM 21.0955, as indicated by the decrease in fasting urinary Ca excretion from 64.0 +/- 7.3 to 6.7 +/- 3.1 nmol/ml GFR, was associated with a change in plasma Ca from 2.97 +/- 0.10 to 2.63 +/- 0.16 mmol/l. However, the relationship between urinary Ca excretion and plasma Ca was not altered, either at endogenous plasma Ca concentration or during the acute infusion of Ca. Similarly, an index of renal tubular reabsorption of Ca calculated from the slope of the linear portion of the relationship between urinary Ca and plasma Ca, which was increased by PTHrP administration, was not influenced by BM 21.0955 therapy (2.59 +/- 0.15 vs. 2.55 +/- 0.11 mmol/l GFR). These results indicate that BM 21.0955, which is one of the most potent bisphosphonates inhibiting bone resorption, did not affect the renal tubular reabsorption of Ca enhanced by PTHrP.

Absorption↗

PubMed1992

Tyrosine phosphorylation selectively regulates renal cellular phosphate transport. Evidence that it mediates the stimulatory effect of insulin-like growth factor-1.

The signal transduction mechanism responsible for the stimulation of the transport of inorganic phosphate (Pi) in response to mitogens is not known. In the present study, the changes in both Pi transport and tyrosine phosphorylation activity were determined in response to orthovanadate (VO4), an insulin-like agent and genistein, a specific inhibitor of tyrosine kinase activity. The results indicate that in opossum kidney epithelia, VO4 stimulated and genistein inhibited Pi transport dose dependently. The characteristics of the VO4 effect were quite similar to those described for insulin-like growth factor-1 (IGF-1) in terms of time course, selectivity (no effect on the Na-alanine transport), and dependency of the de novo synthesis of proteins. The effects of VO4 and IGF-1 on Pi transport, when tested at submaximal and maximal concentrations, respectively, were not additive suggesting that these two agents act through a common regulatory mechanism. As previously shown with IGF-1, the VO4 effect on Pi transport was additive to that of the maximal effect of Pi deprivation. Changes in tyrosine phosphorylation activity were tested in purified plasma membrane isolated from confluent OK cells using the polymer Glu:Tyr (4:1) as exogenous substrate. VO4 markedly enhanced whereas genistein inhibited the tyrosine kinase activity. The VO4 effect was dose dependent (0.1-1.0 mM), a concentration range similar to that eliciting the Pi transport response. The change in Pi transport was highly correlated with the variation in the tyrosine kinase activity induced by either vanadate (R = 0.969 P less than 0.01) or genistein (R = 0.992, P less than 0.01). In conclusion, VO4, an insulin-like agent and genistein, a specific inhibitor of tyrosine kinase activity selectively altered cellular Pi transport. These changes in Pi transport were associated with a dose-related alteration in tyrosine kinase activity measured in purified plasma membrane. The characteristics of the vanadate effects on Pi transport are similar to those reported for IGF-1 suggesting an important role of this signal transduction mechanism in mediating changes in Pi transport in response to mitogenic factors such as IGF-1.

Animals↗

PubMed1992

Resistance to parathyroid hormone-induced inhibition of inorganic phosphate transport in opossum kidney cells cultured in low inorganic phosphate medium.

Renal resistance to the phosphaturic action of parathyroid hormone (PTH) is observed during dietary deprivation of inorganic phosphate (Pi) in vivo. In the present work, the influence of short (3 h)- or long (72 h)-term deprivation of Pi on the effect of bovine PTH (bPTH(1-34)) on both Na-dependent Pi transport and cyclic AMP(cAMP) production was examined in cultured opossum kidney epithelium. Na-dependent Pi transport increased by 100% in cells exposed to low Pi medium containing no Pi (LPM) for 3 h, as compared with transport in high Pi medium containing 2 mmolPi/l (HPM). In response to a submaximal dose (1 nmol/l) of bPTH(1-34), Na-dependent Pi transport was similarly inhibited by about 40% in LPM and HPM. This inhibition was preceded by increased cAMP production which was identical in LPM and HPM. In opossum kidney cells exposed for 72 h to LPM, Na-dependent Pi transport was also increased by 100% compared with that in HPM. However, bPTH(1-34) added at 1 nmol/l did not induce any significant change in Na-dependent Pi transport or cAMP. Stimulation of cAMP could only be elicited at bPTH(1-34) concentrations higher than 1 nmol/l. Such a reduced cAMP response was also observed with forskolin in cells incubated for 72 h in LPM. The cellular resistance to the generation of cAMP was associated with a significantly lower level of ATP in cells cultured for 72 h in LPM compared with ATP levels in HPM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1992

Actions of parathyroid hormone and parathyroid hormone-related protein.

By interacting with a structurally identical receptor, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) display a common spectrum of action on the transport of mineral elements in bone and kidney. In vivo, PTH/PTHrP similarly reduce the renal tubular reabsorption of inorganic phosphate (Pi) and increase that of calcium. The hypercalcemic effect of PTHrP is due to an increase in both bone resorption and renal calcium reabsorption, the latter through a sodium-independent mechanism. The PTHrP-stimulated bone resorption can be totally inhibited by bisphosphonate therapy. Despite that, the fall in calcemia is moderate, indicating that the PTHrP main hypercalcemic action is due to the stimulation of the renal transport of calcium. For identical effects on renal ionic transports, PTHrP appears to less stimulate bone formation than PTH. These experimental findings are similar to clinical observations in patients with primary hyperparathyroidism or with solid malignant tumors. In vitro, the effects of PTH(1-34), PTHrP(1-34) and PTHrP(1-141) on cAMP production and sodium-dependent phosphate transport (NaPiT) are similar in kidney cells, where NaPiT is specifically inhibited by either peptide. This effect is attenuated by the competitive inhibitor [D-Trp12,Tyr34]bPTH(7-34)amide. Transforming growth factor-alpha similarly modulates the cAMP and NaPiT responses to PTH/PTHrP. In cultured mammary cells isolated from lactating rats, PTHrP elicits a 2-fold increase of cAMP production. Various products of bone and stromal cells, and of leukocytes, such as Interleukin-6 or Tumor necrosis factor-alpha, as well as high extracellular calcium concentration enhance PTHrP production by cultured lung squamous cell carcinoma and Leydig tumor cells, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

[IGF-1 and phosphate homeostasis during growth].

Inorganic phosphate (Pi) is an essential determinant of cellular growth and replication. IGF-1, a growth hormone dependent factor, enhances at the kidney level both the tubular reabsorption of inorganic phosphate (Pi) and the production of 1,25-dihydroxyvitamin D3. Through these two renal actions IGF-1 increases the extracellular concentration of Pi. Consequently, the amount of Pi available for cellular growth and bone mineral deposition is maintained at a higher level as compared to the concentration prevailing during the adult life. Thus, IGF-1 appears to play a pivotal role in the control of Pi economy, particularly during growth.

Animals↗

PubMed1991

Characterization of a Pi transport system in cartilage matrix vesicles. Potential role in the calcification process.

The mechanisms by which calcium (Ca2+) and inorganic phosphate (Pi) accumulate into matrix vesicles (MV) have not been elucidated. In the present study the characteristics of Pi uptake into MV isolated from mildly rachitic chicken growth plate cartilage have been investigated. The results indicate that Pi accumulates into MV mainly via a Na(+)-dependent Pi transport system. In the absence of NaCl in the extravesicular medium, Pi uptake was a nonsaturable process. In the presence of 150 mM NaCl, the initial rate of Pi uptake was 4.38 +/- 1.02-fold higher than with 150 mM choline chloride (mean +/- S.E., n = 8, p less than 0.005). Other cations showed partial activity to drive Pi into MV as compared to Na+:Li+ (64.4%) greater than K+ (39.8%) greater than choline (39.0%) greater than tetramethylammonium (30.0%) greater than N-methylglucamine (26.3%). Na(+)-dependent Pi transport activity displayed saturability towards increasing extra-vesicular concentrations of Na+ and Pi. The apparent Km for Pi was 0.68 +/- 0.16 mM. The Na+ concentration producing half-maximum Pi transport activity was 106.2 +/- 11.0 mM. Kinetic analysis suggests that Na+ interacts with the Pi carrier with a stoichiometry of more than one Na+ ion with one Pi molecule. In MV isolated from normal chicken growth plate cartilage, this Na(+)-dependent Pi transport system was barely expressed. In contrast to the effect on Pi uptake by MV, the activity of alkaline phosphatase was not changed when NaCl was substituted for choline chloride in the assay medium. In addition to this observation which suggests that this enzyme is not related to the Pi transport activity described in this study, levamisole, which inhibited alkaline phosphatase activity did not affect the Na(+)-dependent uptake of Pi. Both arsenate and phosphonoformic acid, two inhibitors of the epithelial Na(+)-dependent Pi transport systems, were active inhibitors of the Na(+)-dependent Pi uptake by MV with a higher potency for phosphonoformic acid. Associated with the expression of a facilitated Na(+)-coupled Pi transport in MV, in vitro calcification assessed by 45Ca2+ uptake also showed a marked dependence on extravesicular sodium. This relationship was markedly attenuated in MV isolated from normal chicken growth plate cartilage expressing a weak Na(+)-facilitated Pi transport activity. In conclusion, a saturable Na(+)-dependent Pi carrier has been characterized which facilitates Pi transport in MV. Its potential role for Ca-Pi accumulation into MV and subsequent development of vesicular calcification followed by mineralization of the osteogenic matrix is proposed and remains to be further investigated.

Alkaline Phosphatase↗

PubMed1991

Stimulation by parathyroid hormone-related protein and transforming growth factor-alpha of phosphate transport in osteoblast-like cells.

Parathyroid hormone (1-34) [PTH-(1-34)] has been shown to stimulate sodium-dependent phosphate transport (NaPiT) in UMR-106 osteoblast-like cells through a cAMP-dependent mechanism. Whether a synthetic amino-terminal fragment of parathyroid hormone-related protein (PTHrP) or the full-length molecule, which are recognized to interact with the same receptor as PTH, affect NaPiT in the same way is not known. We investigated and compared the effects of bPTH-(1-34), PTHrP-(1-34), and PTHrP-(1-141) on NaPiT and cAMP production in the osteoblastic cell line UMR-106. Each of the three peptides increased cAMP production and exerted a concentration-dependent stimulation of NaPiT after incubation for 4-6 h. We also studied the effect of transforming growth factor-alpha (TGF-alpha), which is another tumoral product secreted by certain hypercalcemia-associated tumors, on NaPiT and the TGF-alpha-induced modulation of the response to PTHrP or PTH. TGF-alpha caused a 30% stimulation of NaPiT, which remained stable from 6 to 24 h, by a cAMP-independent mechanism. In contrast, TGF-alpha attenuated cAMP production stimulated by PTH, PTHrP-(1-34), or PTHrP-(1-141). PTHrP or PTH did not further increase NaPiT in TGF-alpha-treated cells. These results indicate that NaPiT, a possibly important function of osteoblastic cells, was similarly affected by PTH and PTHrP. TGF-alpha increased NaPiT and modulated in a similar way the effects of both PTH and PTHrP.

Alanine↗

PubMed1991

Fluoride selectively stimulates Na-dependent phosphate transport in osteoblast-like cells.

The influence of fluoride (F) on the transport of Pi was investigated in the osteoblast-like cell line UMR-106. Exposure of cells to F induced a dose-related stimulation of the Na-coupled Pi transport. Pi transport was significantly increased 6 h after 1 mM F incubation, with maximal response observed at 24 h (F 38.0 +/- 2.3, vehicle 19.8 +/- 1.2 pmol.micrograms DNA-1.4 min-1; P less than 0.001). Na-dependent alanine transport was not changed by F. The selective effect of F on Pi transport was not associated with changes in adenosine 3',5'-cyclic monophosphate, cell proliferation, or alkaline phosphatase activity. However, it was completely blunted by inhibiting translational processes with cycloheximide. Furthermore, F enhanced the stimulatory effect on Pi transport of various mitogens such as fetal calf serum, insulin, and insulin-like growth factor I. In conclusion, F can selectively enhance the activity of the Pi transport system present in the plasma membrane of UMR 106 osteoblast-like cells by a mechanism that probably involves newly synthetized proteins.

Alanine↗

PubMed1990

Effect of transforming growth factor-alpha and parathyroid hormone-related protein on phosphate transport in renal cells.

The decrease in plasma Pi concentration and in Pi tubular reabsorption that is often encountered in malignant hypercalcemia may be ascribed to a tumor-produced parathyroid hormone (PTH)-related protein. However, tumors are known to synthesize a variety of substances, among which is transforming growth factor-alpha (TGF-alpha). We investigated the effects of TGF-alpha on Na-dependent Pi transport and on the response to PTH-related protein in cultured opossum renal epithelial cells. TGF-alpha caused a concentration- and time-dependent decrease in Na-dependent Pi transport. The inhibition of Na-dependent Pi transport was detectable by 14 h of incubation and maximal by 24 h. At that time, a concentration of 10 ng/ml of TGF-alpha produced a 35 +/- 1% inhibition. This was not associated with any change in prostaglandin production. The adenosine 3',5'-cyclic monophosphate (cAMP) response to PTH-related protein, PTH, prostaglandin E2 or forskolin, but not to pertussis toxin, was diminished in cells treated with TGF-alpha for 24 h. Similar effects on Na-dependent Pi transport and cAMP production were observed in cells incubated with epidermal growth factor. The inhibition of Na-dependent Pi transport induced by either PTH-related protein or PTH was reduced after incubation with TGF-alpha. Thus two different tumoral products, TGF-alpha and PTH-related protein, are each capable of inhibiting Na-dependent Pi transport in cultured renal cells. Both peptides may also interact and influence the effects of each other on renal Pi transport.

Adenylyl Cyclases↗

PubMed1990

Stimulatory effect of insulin-like growth factor-1 on renal Pi transport and plasma 1,25-dihydroxyvitamin D3.

Administration of GH increases both the tubular reabsorption of inorganic phosphate (Pi) and the plasma level of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. These two effects could be induced by a common mediator, possibly the GH-generated insulin-like growth factor 1 (IGF-1). In the present work, the influence of recombinant human IGF-1 on renal Pi transport and plasma 1,25-(OH)2D3 was examined in hypophysectomized (HPX) rats. IGF-1, infused by miniosmotic pump at the dose of 10 micrograms/h for 6 days, significantly increased the maximal tubular reabsorption of Pi per unit volume of glomerular filtrate (max TRPi/m1GFR): IGF-1 3.50 +/- 0.16; vehicle: 2.78 +/- 0.14 mumol/m1GFR, P less than 0.005. The response was associated with a marked stimulation of plasma 1,25-(OH)2D3 (IGF-1; 409 +/- 23; vehicle: 208 +/- 22 pmol/liter, P less than 0.001). As previously reported for GH, IGF-1 also increased GFR and reduced urinary sodium excretion. In brush border membrane vesicles isolated from renal cortex of HPX rats, the Na-dependent Pi transport was stimulated by IGF-1. Neither the Na-dependent glucose transport nor that of alanine was affected by the growth factor. The stimulatory effect of IGF-1 on maxTRPi/m1GFR was also expressed in thyroparathyroidectomized (TPTX) HPX rats (IGF-1: 5.20 +/- 0.29; vehicle: 3.88 +/- 0.37 mumol/m1GFR, P less than 0.025). In conclusion, administration of IGF-1 in HPX rats mimics the stimulatory effects of GH on maxTRPi/m1GFR and on plasma 1,25-(OH)2D3. As described for GH the change in maxTRPi/m1GFR is mediated by a PTH independent mechanism and is expressed at the level of the luminal membrane of proximal tubules. These results suggest that IGF-1 could be an important factor in the control of Pi metabolism, particularly during growth, and might play a significant role in mediating the effect of GH on the renal handling of Pi and production of 1,25-(OH)2D3.

Absorption↗

PubMed1990

Action of tumoral PTH-related peptide on phosphate and calcium transport.

The recently identified parathyroid hormone-related peptide (PTHrP) exerts several actions on the transport of bone mineral elements. In vitro, the effects of the synthetic amino-terminal fragment of the parathyroid hormone-related protein PTHrP (1-34) on renal cyclic AMP production, Na-dependent Pi transport and Na+/H+ exchange appear to be very similar to PTH (1-34). In vivo, in thyroparathyroidectomized rats, PTHrP reduces the tubular Pi reabsorptive capacity (TmPi/GFR) and thereby lowers the level of plasma Pi. PTHrP (1-34) brings about a dose-dependent elevation in the level of plasma Ca. The hypercalcemic effect of PTHrP (1-34) is due to both an increase in bone Ca resorption, as assessed by an increment in fasting urinary Ca, and an elevation in renal Ca reabsorption. Like PTH, the tumoral peptide does not significantly affect the overall tubular reabsorption of Na. The PTHrP-induced increase in bone Ca resorption is completely inhibitable by diphosphonate therapy. Despite this efficacious antiosteolytic response the fall in calcemia is moderate since the marked effect of PTHrP on the renal transport of Ca is maintained under diphosphonate therapy. These experimental findings are similar to clinical observations previously made with several types of solid tumors.

Biological Transport↗

PubMed1990

[The role of a parathyroid hormone analogue in the pathogenesis of malignant hypercalcemia].

Patients with malignant hypercalcemia can display not only an increase in bone resorption, but also changes in the renal tubular reabsorption of calcium and phosphate similar to those found in primary hyperparathyroidism. A protein of tumoral origin likely responsible for this syndrome has been described. Even if produced by another gene than parathyroid hormone, it shares a homology in the aminoterminus and seems to exert a similar spectrum of action. Besides its role in malignant hypercalcemia, this analogue may be involved in physiological regulatory processes.

Humans↗

PubMed1990

Phosphate transport adaptation in rat jejunum and plasma level of 1,25-dihydroxyvitamin D3.

Intestinal absorption of inorganic phosphate (Pi) increases in response to a reduction in the dietary supply of Pi. In this work this adaptive response has been characterized in jejunal brush border membrane vesicles and studied in temporal relationship with the change in the plasma level of 1,25(OH)2D3. The results indicate that in rat jejunal brush border membrane vesicles the activity of the sodium-dependent Pi transport system is stimulated by a low Pi diet. This adaptive response was the result of an increase in the Vmax and a reduction in the Km of the cotransport system. This change in Pi transport was correlated with an increase in the circulating level of 1,25(OH)2D3 in a time-related fashion. In conclusion, these results are consistent with the notion that Pi restriction leads to an increase in Pi transport activity in the luminal membrane of the intestine. A time course study suggests that the elevation in plasma 1,25(OH)2D3 might be involved in the adaptation of the intestinal Pi transport system to Pi restriction.

Adaptation, Physiological↗

PubMed1989

Role of bone and kidney in parathyroid hormone-related peptide-induced hypercalcemia in rats.

A protein responsible for the biochemical syndrome similar to primary hyperparathyroidism associated with certain tumors has been recently characterized and its effects at the level of bone and kidney reported. However, the relative role of tubular reabsorption of calcium (Ca) and bone resorption in the pathogenesis of hypercalcemia induced by this factor is still debated. We investigated the effects of a synthetic amino-terminal fragment of parathyroid hormone-related protein [PTHrP-(1-34)] administered chronically by intraperitoneal osmotic minipumps in thyroparathyroidectomized (TPTX) rats. Clearance studies performed on day 6 of treatment after a 24 h fast revealed an increase in renal tubular reabsorption of Ca and a decrease in renal tubular reabsorption of phosphate (Pi), accompanied by an increase in cAMP excretion. PTHrP-(1-34) (90 pmol/h) stimulated bone resorption as evaluated by an increment in fasting urinary Ca excretion. Although the bone resorption inhibitor aminopropylidene diphosphonate fully corrected urinary Ca excretion and reduced plasma Ca from 3.04 +/- 0.07 to 2.44 +/- 0.21 mM (p less than 0.05), this latter value remained considerably higher than in TPTX control rats (1.54 +/- 0.12 mM, p less than 0.01). In contrast, when the agent WR-2721, which is known to decrease the renal tubular reabsorption of Ca by a PTH-independent mechanism, was given, a further drop in plasma Ca and an increase in urinary Ca excretion were observed. These findings are similar to those found in animals implanted with the hypercalcemic Leydig cell tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

Amifostine↗

PubMed1989

Regulation of Na-dependent Pi transport by parathyroid hormone in osteoblast-like cells.

In the present work we investigated the influence of parathyroid hormone (PTH) on the transport of inorganic phosphate (Pi) in the osteoblast-like cell line UMR-106. Pi was transferred from the extra- to the intracellular compartment by means of a Na-dependent transport system with an apparent binding affinity for both Pi and Na similar to that recently observed in the osteoblast-like cell line ROS 17/2.8 (Calcif. Tissue Int. 43: 83-87, 1988). Exposure of confluent UMR-106 cells to PTH (10(-9)-10(-7) M) induced a concentration-related stimulation of the Na-dependent Pi transport (NaPiT). An increase in NaPiT was observed after a 1-h exposure to 10(-7) M PTH, with the maximal response occurring at 4-6 h. (PTH, 35.6 +/- 0.3; vehicle, 27.4 +/- 0.2 pmol.microgram DNA-1.4 min-1, P less than 0.001). The stimulatory effect of PTH on NaPiT was not associated with a change in the Na-dependent alanine transport. A positive correlation was observed between the increase of NaPiT and that of cAMP in response to various concentrations of PTH. Stimulation of cAMP by forskolin (10(-4) M) mimicked the effect of PTH on NaPiT. Kinetic analysis of the PTH-induced stimulation of NaPiT indicated an increase in Vmax (PTH, 226.9 +/- 6.9; vehicle, 182.9 +/- 1.9 pmol Pi/microgram DNA, P less than 0.001), with no change in Km. The increase in NaPiT by either PTH or forskolin was followed by a transient inhibition from 6 to 24 h that was associated with a decrease in the Na-dependent alanine transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗

PubMed1989

Insulin-like growth factor I stimulates Na-dependent Pi transport in cultured kidney cells.

The effect of recombinant insulin-like growth factor I (IGF-I/somatomedin C) on the transport of inorganic phosphate (Pi) was studied in cultured kidney epithelia. In opossum kidney (OK) epithelia, IGF-I (5 x 10(-10) to 10(-7) M) induced a dose-related stimulation of the Na-dependent Pi transport (NaPiT). A maximal response was observed at 10(-7) M (IGF-I 1.64 +/- 0.12; vehicle 0.90 +/- 0.02 nmol.mg protein-1. 4 min-1, P less than 0.001). Kinetic analysis of the stimulatory effect of IGF-I on NaPiT indicated an increase in Vmax and no change in Km. Insulin also stimulated NaPiT in OK epithelia but only at concentrations 20-40 times higher than IGF-I. The effect of IGF-I on Pi transport was detectable in less than 30 min with a maximal response occurring after 4-5 h. It was selective for NaPiT, since the Na-dependent alanine transport was not affected by IGF-I. Inhibition of protein synthesis by either cycloheximide or cordycepin markedly attenuated the stimulatory effect of IGF-I on NaPiT. The cellular adenosine 3',5'-cyclic monophosphate content was not modified by the growth factor. In conclusion, these data indicate that IGF-I increases NaPiT selectively through a mechanism that involves de novo protein synthesis. These observations suggest that growth and growth hormone-related stimulation of renal Pi transport could be mediated by IGF-I.

Animals↗

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↗