Renal Pi Handling Research Articles

The calcium-sensing receptor has only a parathyroid hormone-dependent role in the acute response of renal phosphate transporters to phosphate intake.

The kidney controls systemic inorganic phosphate (Pi) levels by adapting reabsorption to Pi intake. Renal Pi reabsorption is mostly mediated by sodium-phosphate cotransporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) that are tightly controlled by various hormones including parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). PTH and FGF23 rise in response to Pi intake and decrease NaPi-IIa and NaPi-IIc brush border membrane abundance enhancing phosphaturia. Phosphaturia and transporter regulation occurs even in the absence of PTH and FGF23 signaling. The calcium-sensing receptor (CaSR) regulates PTH and FGF23 secretion, and may also directly affect renal Pi handling. Here, we combined pharmacological and genetic approaches to examine the role of the CaSR in the acute phosphaturic response to Pi loading. Animals pretreated with the calcimimetic cinacalcet were hyperphosphatemic, had blunted PTH levels upon Pi administration, a reduced Pi-induced phosphaturia, and no Pi-induced NaPi-IIa downregulation. The calcilytic NPS-2143 exaggerated the PTH response to Pi loading but did not abolish Pi-induced downregulation of NaPi-IIa. In mice with a dominant inactivating mutation in the Casr (CasrBCH002), baseline NaPi-IIa expression was higher, whereas downregulation of transporter expression was blunted in double CasrBCH002/PTH knockout (KO) transgenic animals. Thus, in response to an acute Pi load, acute modulation of the CaSR affects the endocrine and renal response, whereas chronic genetic inactivation, displays only subtle differences in the downregulation of NaPi-IIa and NaPi-IIc renal expression. We did not find evidence that the CaSR impacts on the acute renal response to oral Pi loading beyond its role in regulating PTH secretion.NEW & NOTEWORTHY Consumption of phosphate-rich diets causes an adaptive response of the body leading to the urinary excretion of phosphate. The underlying mechanisms are still poorly understood. Here, we examined the role of the calcium-sensing receptor (CaSR) that senses both calcium and phosphate. We confirmed that the receptor increases the secretion of parathyroid hormone involved in stimulating urinary phosphate excretion. However, we did not find any evidence for a role of the receptor beyond this function.

Molecular Control of Growth-Related Sodium-Phosphate Co-transporter (SLC34A3)

The type IIa sodium-dependent inorganic phosphate transporter (NaPi-IIa) has a central regulatory role in inorganic phosphate (Pi) homeostasis. Many studies have reported on the functions and regulatory mechanisms of NaPi-IIa. NaPi-IIc, however, was initially identified as a NaPi transporter required for growth in rodents. The gene encoding NaPi-IIc is causative for hereditary hypophosphatemic rickets with hypercalciuria and considered to be a critical NaPi transporter in the human kidney. However, the physiological roles and regulatory mechanisms of NaPi-IIc are not sufficiently elucidated. Recent studies show that NaPi-IIc is tightly regulated by a variety of agonists and physiological conditions via partially defined molecular mechanisms, including transcriptional and posttranscriptional regulation, protein phosphorylation, trafficking (endocytosis, exocytosis, and recycling), and the association of NaPi-IIc with interacting protein complexes. These data provide further information about understanding of human renal Pi handling. Here, we review recent findings regarding the molecular control of NaPi-IIc transporters.

Klotho/fibroblast growth factor 23- and PTH-independent estrogen receptor-α-mediated direct downregulation of NaPi-IIa by estrogen in the mouse kidney.

Estrogen treatment causes renal phosphate (Pi) wasting and hypophosphatemia in rats and humans; however, the signaling mechanisms mediating this effect are still poorly understood. To determine the specific roles of estrogen receptor isoforms (ERα and ERβ) and the Klotho pathway in mediating these effects, we studied the effects of estrogen on renal Pi handling in female mice with null mutations of ERα or ERβ or Klotho and their wild type (WT) using balance studies in metabolic cages. Estrogen treatment of WT and ERβ knockout (KO) mice caused a significant reduction in food intake along with increased renal phosphate wasting. The latter resulted from a significant downregulation of NaPi-IIa and NaPi-IIc protein abundance. The mRNA expression levels of both transporters were unchanged in estrogen-treated mice. These effects on both food intake and renal Pi handling were absent in ERα KO mice. Estrogen treatment of Klotho KO mice or parathyroid hormone (PTH)-depleted thyroparathyroidectomized mice exhibited a significant downregulation of NaPi-IIa with no change in the abundance of NaPi-IIc. Estrogen treatment of a cell line (U20S) stably coexpressing both ERα and ERβ caused a significant downregulation of NaPi-IIa protein when transiently transfected with a plasmid containing full-length or open-reading frame (ORF) 3'-untranslated region (UTR) but not 5'-UTR ORF of mouse NaPi-IIa transcript. In conclusion, estrogen causes phosphaturia and hypophosphatemia in mice. These effects result from downregulation of NaPi-IIa and NaPi-IIc proteins in the proximal tubule through the activation of ERα. The downregulation of NaPi-IIa by estrogen involves 3'-UTR of its mRNA and is independent of Klotho/fibroblast growth factor 23 and PTH signaling pathways.

Compensatory regulation of the sodium/phosphate cotransporters NaPi-IIc (SCL34A3) and Pit-2 (SLC20A2) during Pi deprivation and acidosis

The role of four Pi transporters in the renal handling of Pi was analyzed using functional and molecular methods. The abundance of NaPi-IIa, NaPi-IIc, and Pit-2 was increased by 100% in kidney from rats on a 0.1% Pi diet, compared to a 0.6% Pi diet. Pit-1 was not modified. Type II-mediated Pi uptake in Xenopus oocytes increased as the pH of the uptake medium increased, and the opposite occurred with Pit-1 and Pit-2. At pH 6.0, Pi uptake mediated through type II was approximately 10% of the uptake at pH 7.5, but the uptake through Pit-2 was 250% of the activity at pH 7.5. Real brush-border membrane vesicles (BBMV) responded to pH changes following the same pattern as type II transporters. Adaptation to a 0.1% Pi diet was accompanied by a 65% increase in the V (max) of BBMV Pi transport at pH 7.5, compared to a 0.6% Pi diet. The increase was only 11% at pH 6.0. Metabolic acidosis increased the expression of NaPi-IIc and Pit-2 in animals adapted to a low Pi diet, and phosphaturia was only observed in control diet animals. The combination of the pH effect, Pi adaptation, and metabolic acidosis suggests very modest involvement of Pit-2 in renal Pi handling. Real-time PCR and mathematical analyses of transport findings suggest that NaPi-IIa RNA accounts for 95% of all Pi transporters and that type II handles 97% of Pi transport at pH 7.5 and 60% of Pi transport at pH 6.0, depending on the pH and the physiological conditions.

Magnesium stimulates renal phosphate reabsorption

In the kidney, approximately 80% of the filtered phosphate (Pi) is reabsorbed along the proximal tubule. Changes in renal Pi reabsorption are associated with modulation of the sodium-dependent Pi cotransporter type IIa (NaPi-IIa) and type IIc (NaPi-IIc) protein abundance in the brush-border membrane (BBM) of proximal tubule cells. NaPi-IIa is mainly regulated by dietary Pi intake and parathyroid hormone (PTH). The purpose of the present study was to elucidate the effect of alteration in dietary magnesium (Mg2+) intake on renal Pi handling. Urinary Pi excretion and renal expression of NaPi-IIa and NaPi-IIc were analyzed in rats fed a normal (0.2%) or high-Mg2+ (2.5%) diet. A high-Mg2+ diet resulted in decreased renal Pi excretion and increased protein expression of NaPi-IIa and NaPi-IIc. Serum FGF-23 (fibroblast growth factor 23) levels were unchanged under a high-Mg2+ diet. Serum PTH levels were slightly decreased under a high-Mg2+ diet. To examine whether the observed changes in renal Pi reabsorption are PTH dependent, expression of NaPi-IIa and NaPi-IIc was also analyzed in parathyroidectomized (PTX) rats fed a normal or high-Mg2+ diet. In PTX rats, Mg2+ had no significant effect on renal Pi excretion or NaPi-IIa protein expression. Mg2+ increased NaPi-IIc protein expression in PTX rats. This experiment shows for the first time on the molecular level how Mg2+ stimulates renal Pi reabsorption. Under a high-Mg2+ diet, NaPi-IIa expression is dependent on PTH levels, whereas NaPi-IIc expression seems to be independent of PTH levels.

Phosphate transport: Molecular basis, regulation and pathophysiology

Inorganic phosphate (Pi) is fundamental to cellular metabolism and skeletal mineralization. Ingested Pi is absorbed by the small intestine, deposited in bone, and filtered by the kidney where it is reabsorbed and excreted in amounts determined by the specific needs of the organism. Two distinct renal Na-dependent Pi transporters, type IIa (NPT2a, SLC34A1) and type IIc (NPT2c, SLC34A3), are expressed in brush border membrane of proximal tubular cells where the bulk of filtered Pi is reabsorbed. Both are regulated by dietary Pi intake and parathyroid hormone. Regulation is achieved by changes in transporter protein abundance in the brush border membrane and requires the interaction of the transporter with scaffolding and signaling proteins. The demonstration of hypophosphatemia secondary to decreased renal Pi reabsorption in mice homozygous for the disrupted type IIa gene underscores its crucial role in the maintenance of Pi homeostasis. Moreover, the recent identification of mutations in the type IIc gene in patients with hereditary hypophosphatemic rickets with hypercalciuria attests to the importance of this transporter in Pi conservation and subsequent skeletal mineralization. Two novel Pi regulating genes, PHEX and FGF23, play a role in the pathophysiology of inherited and acquired hypophosphatemic skeletal disorders and studies are underway to define their mechanism of action on renal Pi handling in health and disease.

Fibroblast Growth Factor-23 Relationship to Dietary Phosphate and Renal Phosphate Handling in Healthy Young Men

The renal handling of inorganic phosphate (Pi) is controlled not only by PTH, but also by hitherto undetermined mechanisms dependent on phosphate intake. Recently, fibroblast growth factor (FGF)-23 was identified as a novel phosphaturic factor in tumor-induced osteomalacia and autosomal-dominant hypophosphatemic rickets. We hypothesized that phosphate intake could influence FGF-23 concomitantly to the changes in renal Pi handling. Twenty-nine healthy males were subjected to a 5-d low-phosphate diet and a phosphate binder, followed by a high-phosphate diet including supplements. Concomitant modifications in calcium intake allowed minimizing PTH changes in response to dietary phosphate. Serum FGF-23 levels significantly decreased on the low-phosphate diet, then increased with the oral phosphate load. Changes in FGF-23 were positively correlated with changes in 24-h urinary Pi excretion and negatively correlated with changes in the maximal tubular reabsorption of Pi and 1,25(OH)(2)D(3) (calcitriol), whereas PTH was not. In multivariate analysis, changes in FGF-23 remained the most significantly correlated to changes in 1,25(OH)(2)D(3) and maximal tubular reabsorption of Pi. Moreover, FGF-23 was positively correlated to serum osteocalcin, a marker of osteoblastic activity. In summary, FGF-23 was inversely related to renal Pi transport and serum calcitriol levels in healthy young men. These data suggest that FGF-23 may be implicated in the physiological regulation of Pi homeostasis in response to dietary phosphate changes, independent of PTH.

The Renal Type IIa Na/P<sub>i</sub> Cotransporter

The type IIa Na/Pi cotransporter mediates proximal tubular brush-border membrane secondary active phosphate (Pi) flux. It is rate limiting in tubular Pi reabsorption and, thus, a final target in many physiological and pathophysiological situations of altered renal Pi handling. In the present short review, we will briefly summarize our current knowledge about the transport mechanism (cycle) as well as particular regions of the transporter protein ("molecular domains") that potentially determine transport characteristics.

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Npt2 gene disruption confers resistance to the inhibitory action of parathyroid hormone on renal sodium-phosphate cotransport.

PTH inhibition of renal sodium-phosphate (Na-Pi) cotransport is associated with the endocytic retrieval of the type II Na-Pi cotransporter, Npt2, from the renal brush border membrane into the late endosomal/lysosomal compartment. The aim of the present study was to determine whether mice homozygous for the disrupted Npt2 gene (Npt2-/-) exhibit decreased renal Pi reabsorption in response to PTH. We demonstrate that PTH has no effect on the serum Pi concentration, fractional excretion of Pi, or Na-dependent Pi transport in renal brush border membrane vesicles in Npt2-/- mice. In contrast, PTH elicits a fall in the serum Pi concentration, an increase in urinary Pi excretion, a decrease in brush border membrane Na-Pi cotransport, and a corresponding reduction in the relative abundance of Npt2 protein in wild-type mice (Npt2+/+). Both Npt2-/- and Npt2+/+ mice exhibit a significant rise in the urinary cAMP/creatinine ratio in response to PTH, indicating that generalized resistance to PTH cannot account for the absence of the PTH response in Npt2-/- mice. In addition, we demonstrate that Pi-depleted normal mice respond to PTH with a decrease in renal brush border membrane Na-Pi cotransport and Npt2 protein, indicating that Pi deficiency per se does not account for PTH resistance in Npt2-/- mice. Taken together, our data provide compelling evidence that Npt2 gene expression is crucial for PTH effects on renal Pi handling.

X-linked hypophosphataemia: a homologous disorder in humans and mice.

X-linked hypophosphatemia is an inherited disorder of phosphate (Pi) homeostasis characterized by growth retardation, rickets and osteomalacia, hypophosphataemia, and aberrant renal Pi reabsorption and vitamin D metabolism. Studies in murine Hyp and Gy homologues have identified a specific defect in Na+-Pi cotransport at the brush border membrane, abnormal regulation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D) synthesis and degradation, and an intrinsic defect in bone mineralization. The mutant gene has been identified in XLH patients, by positional cloning, and in Hyp and Gy mice, and was designated PHEX/Phex to signify a PHosphate-regulating gene with homology to Endopeptidases on the X chromosome. PHEX/Phex is expressed in bones and teeth but not in kidney and efforts are under way to elucidate how loss of PHEX/Phex function elicits the mutant phenotype. Based on its homology to endopeptidases, it is postulated that PHEX/Phex is involved in the activation or inactivation of a peptide hormone(s) which plays a key role in the regulation of bone mineralization, renal Pi handling and vitamin D metabolism.

Proximal tubular Pi-transporter(s): Regulation via internalization/ degradation and resynthesis/insertion

Inorganic phosphate (Pi) is reabsorbed in the proximal tubule by a sodium ion (Na+)-dependent, secondary active transport mechanism. Using an expression-cloning strategy, we have identified 2 different Na+/Pi-cotransporters, type I and type II, located preferentially in the brush border membrane of proximal tubular epithelial cells. Altered brush border membrane expression of the type II Na+/Pi-cotransporter fully accounts for altered renal Pi-handling, such as that which occurs in parathyroid hormone and/or dietary Pi-intake-induced alterations. Down-regulation of transport activity (caused by parathyroid hormone or Pi overload) is related to membrane retrieval and lysosomal degradation, whereas up-regulation of brush border membrane Pi-transport (caused by parathyroid hormone removal; Pi deprivation) is due to membrane insertion, which can be preceded by de novo synthesis of the transporter.

Translated anti-sense product of the Na/phosphate co-transporter (NaPi-II).

The homeostasis of Pi in marine teleosts is maintained by renal Pi secretion as well as by Pi reabsorption. A Na/Pi co-transport system belonging to the NaPi-II protein family is instrumental in tightly controlled renal Pi handling in mammals and fish. We have isolated an NaPi-II related cDNA from winter flounder. It was cloned from a female gonad cDNA library and is 624 bp long. The transcript is expressed in female and male flounder gonads as well as in kidney and intestine, although at very low levels. RNase H digestion experiments revealed an opposite orientation of the transcript with regard to NaPi-II-related mRNA. The anti-sense orientation was confirmed by genomic sequence analysis and Southern blotting. Alluding to the sense transcript, the anti-sense transcript was denoted IPAN. The open reading frame of IPAN encodes a basic protein of 68 amino acid residues. Immunohistochemistry confined the anti-sense related protein, Ipan, to a submembranous compartment of immature oocytes, suggesting a role in oocyte development. In kidney and intestine Ipan is partly co-localized with the Na/Pi co-transporter, implying a regulatory function for the anti-sense protein. However, direct protein-protein interaction could not be established. The existence of a putative open reading frame in other species extends the biological significance of the novel protein.

Peptide hormone action on renal phosphate handling

The phosphorus in plasma is present almost entirely as inorganic phosphate (Pi) and renal handling of Pi plays a major role in regulating the plasma level of Pi. About 95% of plasma Pi is ultrafilterable at the glomerulus and, under normal conditions, about 20% of the filtered Pi is excreted in the urine. Secretion of Pi does not appear to be an important transport process in the mammalian kidney. The convoluted and straight segments of the proximal tubule are the major nephron sites where filtered Pi is reabsorbed. Reabsorption in the proximal tubule is a saturable process, and the Tm is influenced by the prevailing metabolic and hormonal conditions [1]. The peptide hormones that influence renal Pi handling exert their effects primarily by changing Pi reabsorption in the proximal tubule. The initial, probably ratelimiting, step in Pi reabsorption is entry into the proximal tubule cell through the action of a Na/Pi cotransport system in the apical brush border membrane (BBM). The efflux (and influx) step across the basolateral membrane is less well-defined and more than one transport mechanism may be involved. The evidence for these steps in transcellular transport has been reviewed recently [2, 3]. Regulation of tubular reabsorption of Pi by many different factors appears to be accomplished, at least in part, through changes in the Na/Pi cotransport capacity of the apical BBM. This review is focused on the regulation of this step by peptide hormones and growth factors (Table 1).

Growth factors and renal regulation of phosphate transport.

During the development of vertebrates, the extracellular concentration of inorganic phosphate (Pi) is maintained at a higher level than during adult life. This elevation is probably essential for both cellular growth and mineralization of the skeleton. A high tubular Pi transport capacity (maxTRPi/GFR) and a high plasma level of 1,25-dihydroxyvitamin D3 are considered to play a major role in the high Pi retention observed during growth. Experimental studies have shown that the high maxTRPi/GFR observed in growing young compared with adult individuals is not associated with differences in other renal functions, suggesting the existence of a selective homeostatic process. Growth hormone (GH) had no direct effect on renal Pi reabsorption, indicating that GH stimulation of renal Pi transport in various physiological and pathophysiological conditions is induced by insulin-like growth factor-1 (IGF-1), the mediator of the anabolic effects of GH. In hypophysectomized rats, administration of IGF-1 mimicked the stimulatory effects of GH on maxTRPi per milliliter glomerular filtrate and on plasma 1,25-dihydroxyvitamin D3. As for GH, the change in maxTRPi per milliliter glomerular filtrate induced by IGF-1 was mediated by a parathyroid hormone-independent mechanism and was selectively expressed at the level of the luminal membrane of proximal tubules. These observations are evidence that IGF-1 mediates the effect of GH on the renal handling of Pi and production of 1,25-dihydroxyvitamin D3 and might play a significant role in the control of Pi metabolism during growth. Recent observations suggest that other growth factors might be involved in the regulation of tubular Pi transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian Changes in Plasma Phosphate Concentration, Urinary Phosphate Excretion, and Cellular Phosphate Shifts

The concentration of phosphate (Pi) in plasma, Pi excretion, and the tubular threshold of Pi resorption (TmP/GFR) all increase throughout the day from about 1100 to 0300 h. For plasma [Pi], cosinor analysis yielded the following estimates of the parameters of this pattern (with 95% confidence limits): amplitude = 0.17 (0.07-0.26) mmol/L, phase = peak at 0201 (1127-0342) h, and MESOR = 1.14 (1.11-1.18) mmol/L. The increase in TmP/GFR reflects an underlying change in renal Pi handling, which is not attributable to changes in parathyrin concentrations. The changes in Pi excretion work both for and against the changes in plasma [Pi], at different times. The calculated net nonrenal flux of Pi into the extracellular fluid increases in the morning and remains high until 0300 h, and neither it nor Pi excretion nor plasma [Pi] shows any relation to meals. This illustrates the importance of transient net fluxes of Pi between intracellular and extracellular spaces in the control of hour-to-hour changes of plasma [Pi].

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.

Effect of acute hypercapnia on PTH-stimulated phosphaturia in dietary Pi-deprived rat.

The effects of respiratory acidosis on renal inorganic phosphate (Pi) handling are controversial. Clearance experiments, therefore, were performed in fasted, chronically parathyroidectomized (PTX), dietary Pi-deprived rats. The objectives were twofold: to study the effects of compensated and uncompensated hypercapnia per se on renal Pi excretion and to examine the interaction between acute hypercapnia, dietary Pi, and parathyroid hormone (PTH) on the renal handling of Pi. Acute hypercapnia increased the plasma Pi (delta 2.82 +/- 0.65 mg/dl, P less than 0.05) without altering the glomerular filtration rate (GFR). The FEPi increased (delta 7.26 +/- 0.48%, P less than 0.001) but the TRPi/GFR also increased. PTH (3 U X kg-1 X h-1) superimposed on hypercapnia resulted in a plasma Pi comparable to hypercapnia alone. The FEPi (7.56 +/- 0.78 vs. 24.43 +/- 2.20%; P less than 0.001) was higher and the TRPi/GFR (117 +/- 4 vs. 80 +/- 2 micrograms/min, P less than 0.01) lower, in the former group. PTH infusion during normocapnia resulted in a lower FEPi (0.20 +/- 0.10 vs. 24.43 +/- 2.20%, P less than 0.001) and a higher TRPi/GFR (106 +/- 2 vs. 80 +/- 2 micrograms/min, P less than 0.01) compared with PTH infusion during hypercapnia. Urinary adenosine 3',5'-cyclic monophosphate (cAMP) excretion was similar between the groups. During hypercapnia, when the extracellular acidemia was neutralized, the phosphaturic action of PTH persisted. These studies offer direct evidence that in chronically PTX, dietary Pi-deprived rats, the phosphaturic action of PTH is restored by hypercapnia per se. This effect appears to be independent of extracellular acidemia, changes in the plasma Pi and calcium, urinary pH and Na and cAMP excretion.

Effects of glucagon on renal and extrarenal handling of Pi in rodents: evidence for Pi mobilizing activity.

Glucagon is known to be released during fasting (1) and between meals (2), and it is generally accepted that the presence of this hormone is important in the prevention of hypoglycemia. Furthermore, glucagon has also been found to be phosphaturic in man (3) and animals (4, 5) fed diets containing normal amounts of inorganic phosphate (Pi). Since these phosphaturic effects are associated with decrements in Plasma Pi concentration ([Pi]P1.) one has to conclude that glucagon had acted through a change in the renal handling of Pi.

Mechanisms of NAD action in regulation of renal brush border membrane transport of phosphate.

Many different hormonal and non-hormonal stimuli change the rate of phosphate (Pi) transport across the renal brush border membrane (BBM) (1,2, 3) which probably reflects the central role of proximal tubular reabsorption in renal handling of Pi. Based on considerations of (a) the time required for the effects of these stimuli to induce a response, and (b) whether the response is dependent upon intact de novo protein synthesis, it appears that the various stimuli may act intracellularly through at least two general mechanisms (2).