Intestinal Phosphate Transport Research Articles

Vitamin-D regulation of bone mineralization and remodelling during growth

Vitamin D status relates to two bone diseases, osteomalacia and osteoporosis which arise from distinct pathophysiogical pathways. They can occur in children as well as adults. Osteomalacia or rickets arises from a delay in mineralization and can be caused by severe vitamin D deficiency where the key to curing osteomalacia is the endocrine action of circulating 1,25-dihydroxyvitamin D to normalize the active intestinal transport of calcium and phosphate. Osteoporosis or sub-optimal bone mineral accretion during growth is a risk factor for fracture in children. Current evidence suggests serum 25-hydroxyvitamin D levels between 20 and 80 nmol/L are associated with decreased bone mineral content as a result, at least partly, of reduced vitamin D metabolism and activity within bone cells. The local synthesis of 1,25-dihydroxyvitamin D within bone is necessary to modulate bone resorption and promote bone formation. Thus an adequate vitamin D status is necessary for vitamin D activity within bone to establish a healthy skeleton.

Tracking of Single Microvilli to Study Regulation of the Intestinal Phosphate Transporters

Intestinal phosphate (Pi) uptake is one of the key mechanisms of systemic Pi homeostasis. Modulation of intestinal Pi transport has been recently recognized as an important target in prevention of hyperphosphatemia and the associated cardiovascular complications in Chronic Kidney Disease. Intestinal Pi absorption is mainly mediated by the type IIb sodium-phosphate co-transporter NaPi2b which is expressed in the intestinal apical microvilli. Recent evidences show that agonists of the LXR nuclear hormone receptor inhibit intestinal NaPi transport activity, NaPi2b protein and mRNA abundance, and decrease serum Pi level [1]. However, the detailed mechanisms of how LXR decreases intestinal NaPi transport activity, including the role of changes in membrane cholesterol or PDZ interacting proteins, remain to be determined.In order to study these processes at the molecular level we apply the Modulation Tracking nanoimaging method [2] to microvilli of live cells expressing fluorescently tagged NaPi2b. This technique generalizes the principles of Single Particle Tracking to allow the imaging of extended subcellular structures. Tracking the single microvilli we directly measure their motion, while we also image NaPi2b distribution along the membrane and perform Fluorescence Correlation Spectroscopy techniques (RICS, N&B) in steady state, even if the microvilli are moving. Different dynamic properties, including motility of the microvilli and protein diffusion and clustering, are monitored under stimulation to get insights into the process of intestinal transporters regulation.Work supported in part by NIH R01 DK066029-01A2 (ML, EG and LL), NIH-P41-RR03155 (EG and LL) and P50-GM076516 (EG, MD and LL).

In vitro studies on intestinal calcium and phosphate transport in horses

Transepithelial transport mechanisms play a key role in regulating the absorption and secretion of calcium (Ca 2 + ) and inorganic phosphate (P i) in the gastrointestinal tract. Although intestinal disorders with imbalances in macromineral homeostasis are frequently observed in horses, available data on intestinal Ca 2 + and P i transport are limited. The aim of the present study was to characterize the intestinal Ca 2 + and P i transport functionally by using the in vitro radioisotope tracer technique with Ussing chambers and to identify components involved in Ca 2 + transport at both mRNA and protein level. Among the different intestinal segments, the duodenum showed significant and highest active Ca 2 + absorption. The findings from RT-PCR and Western blot analysis suggest that the epithelial Ca 2 + channel TRPV6, the cytosolic calcium binding protein calbindin-D 9K and the plasma membrane calcium ATPase PMCA may be involved in active transcellular Ca 2 + transport. Regarding the P i transport, the results indicate significant active P i secretion in the jejunum, but the contributing mechanisms remain unclear. A significant inhibiting effect of ouabain as an antagonist of the basolateral Na +/K +-ATPase on the serosal-to-mucosal P i transport suggests a pivotal role of Na + in jejunal P i transport in the horse.

Gut–Bone Interactions and Implications for the Child With Chronic Gastrointestinal Disease

Bone is not simply a framework on which to hang viscera and connective tissue; it is also a dynamic interactive organ system with roles in immunoregulation, adipogenesis, and vascular calcification, among others. Bone is intimately affected by chronic disease, including gastrointestinal disease. The mechanisms for bone loss in conditions such as inflammatory bowel disease, celiac disease, and cystic fibrosis are discussed with regard to the role of the inflammatory response. Furthermore, we raise the issue of effects of inflammation on both intestinal and renal calcium and phosphate transport, although the ways in which these actions affect bone are not explained and require further research. The stress response, a prominent feature following burn injury, is also elucidated and its relation to gastrointestinal disease is examined. We then discuss the importance of knowing the mechanism of bone loss to determine proper prevention and treatment for the bone loss in specific gastrointestinal conditions.

Downregulation of NaPi-IIa and NaPi-IIb Na+-coupled Phosphate Transporters by Coexpression of Klotho

Klotho, a transmembrane protein, protease and hormone has been shown to exert a profound effect on phosphate metabolism. Klotho overexpression lowers and Klotho deficiency increases the plasma phosphate concentration, effects in part attributed to an inhibitory effect of Klotho on the formation of 1,25-dihydroxycholecalciferol (1,25(OH) ₂D₃), the active form of Vitamin D. Beyond that Klotho has been shown to decrease renal tubular phosphate transport more directly. The influence of Klotho on the plasma phosphate concentration contributes to the profound effect of Klotho on ageing and life span. The present study explored whether Klotho influences the major renal tubular (NaPi-IIa) and the major intestinal (NaPi-IIb) phosphate transporters. For functional analysis NaPi-IIa or NaPi-IIb were expressed in Xenopus oocytes both, without or with additional coexpression of Klotho and electrogenic phosphate transport was estimated from the phosphate-induced current (Ip). According to RT-PCR Klotho is expressed in the murine kidney and intestine. Coexpression of Klotho decreased Ip in both NaPi-IIa- and NaPi-IIb-expressing oocytes. Klotho decreased the maximal Ip without appreciably affecting the concentration required for halfmaximal Ip. Treatment of NaPi-IIa- or NaPi-IIb-expressing oocytes with Klotho protein similarly decreased Ip. In conclusion, Klotho down regulates both, renal (NaPi-IIa) and intestinal (NaPi-IIb) phosphate transporters.

Reciprocal Control of 1,25-Dihydroxyvitamin D and FGF23 Formation Involving the FGF23/Klotho System

Fibroblast growth factor 23 (FGF23) is a circulating hormone that is synthesized by osteocytes and osteoblasts. This glycosylated peptide controls phosphate balance by modulating urinary phosphate excretion and indirectly intestinal phosphate absorption by reducing expression of the renal and intestinal sodium phosphate transporters. In a feedback loop, 1,25-dihydroxyvitamin D and phosphate intake control FGF23 production. FGF23 is inactivated by cleavage by a still unidentified enzyme. FGF23 cleavage occurs within cells and probably in the circulation. Klotho, a protein expressed at the cell surface of few organs, forms complexes with FGF receptors, which increases their affinity for FGF23. Klotho is also released into the plasma and urine by an enzymatic cleavage. FGF23 plays a central role in vitamin D metabolism: It inhibits calcitriol synthesis in the kidney and stimulates the catabolism of active vitamin D sterols. In turn, calcitriol stimulates FGF23 and Klotho expression. In chronic kidney diseases, FGF23 concentration increases as GFR declines, whereas Klotho tissue expression decreases. The modifications of FGF23 and Klotho expression are probably involved in the genesis of hyperparathyroidism and the resistance to vitamin D receptor (VDR) activation in chronic kidney disease. Low vitamin D, high FGF23 concentrations, and defects in VDR activation are associated with similar risks, which evoke the possibility that potential FGF23 toxicity might be partly mediated by FGF23-induced decrease in calcitriol or 25-hydroxyvitamin D. Conversely, VDR activators could be used to modulate Klotho or FGF23 expression.

Mechanism of Intestinal Phosphate Transport

Mechanism of Intestinal Phosphate Transport

Phosphate homeostasis and the renal-gastrointestinal axis

Transport of phosphate across intestinal and renal epithelia is essential for normal phosphate balance, yet we know less about the mechanisms and regulation of intestinal phosphate absorption than we do about phosphate handling by the kidney. Recent studies have provided strong evidence that the sodium-phosphate cotransporter NaPi-IIb is responsible for sodium-dependent phosphate absorption by the small intestine, and it might be that this protein can link changes in dietary phosphate to altered renal phosphate excretion to maintain phosphate balance. Evidence is also emerging that specific regions of the small intestine adapt differently to acute or chronic changes in dietary phosphate load and that phosphatonins inhibit both renal and intestinal phosphate transport. This review summarizes our current understanding of the mechanisms and control of intestinal phosphate absorption and how it may be related to renal phosphate reabsorption; it also considers the ways in which the gut could be targeted to prevent, or limit, hyperphosphatemia in chronic and end-stage renal failure.

Rapamycin-induced phosphaturia

The mammalian target of rapamycin (mTOR) is known to stimulate a variety of transport mechanisms including the intestinal phosphate transporter NaPi-IIb. The present study was performed to elucidate whether mTOR similarly regulates the major renal tubular phosphate transporter NaPi-IIa. To this end, NaPi-IIa was expressed in Xenopus oocytes with or without mTOR and phosphate transport estimated from phosphate-induced (1 mM) current (I(pi)). As a result, I(pi) was observed in NaPi-IIa-expressing but not in H(2)O-injected Xenopus oocytes. Co-expression of mTOR significantly enhanced I(pi) in NaPi-IIa-expressing Xenopus oocytes, an effect abrogated by treatment with rapamycin (50 nM for the last 24 h of incubation). In a second series of experiments, the effect of rapamycin was analysed in mice. The in vivo administration of rapamycin (3 microg/g body weight/day) for 3 days resulted in phosphaturia in mice despite a tendency of plasma phosphate concentration to decrease. mTOR contributes to the regulation of renal phosphate transport, and rapamycin thus influences phosphate balance.

Dietary Fructose Inhibits Intestinal Calcium Absorption and Induces Vitamin D Insufficiency in CKD

Renal disease leads to perturbations in calcium and phosphate homeostasis and vitamin D metabolism. Dietary fructose aggravates chronic kidney disease (CKD), but whether it also worsens CKD-induced derangements in calcium and phosphate homeostasis is unknown. Here, we fed rats diets containing 60% glucose or fructose for 1 mo beginning 6 wk after 5/6 nephrectomy or sham operation. Nephrectomized rats had markedly greater kidney weight, blood urea nitrogen, and serum levels of creatinine, phosphate, and calcium-phosphate product; dietary fructose significantly exacerbated all of these outcomes. Expression and activity of intestinal phosphate transporter, which did not change after nephrectomy or dietary fructose, did not correlate with hyperphosphatemia in 5/6-nephrectomized rats. Intestinal transport of calcium, however, decreased with dietary fructose, probably because of fructose-mediated downregulation of calbindin 9k. Serum calcium levels, however, were unaffected by nephrectomy and diet. Finally, only 5/6-nephrectomized rats that received dietary fructose demonstrated marked reductions in 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) levels, despite upregulation of 1alpha-hydroxylase. In summary, excess dietary fructose inhibits intestinal calcium absorption, induces marked vitamin D insufficiency in CKD, and exacerbates other classical symptoms of the disease. Future studies should evaluate the relevance of monitoring fructose consumption in patients with CKD.

Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate

Hyperphosphatemia associated with chronic kidney disease is one of the factors that can promote vascular calcification, and intestinal P(i) absorption is one of the pharmacological targets that prevents it. The type II Na-P(i) cotransporter NaPi-2b is the major transporter that mediates P(i) reabsorption in the intestine. The potential role and regulation of other Na-P(i) transporters remain unknown. We have identified expression of the type III Na-P(i) cotransporter PiT-1 in the apical membrane of enterocytes. Na-P(i) transport activity and NaPi-2b and PiT-1 proteins are mostly expressed in the duodenum and jejunum of rat small intestine; their expression is negligible in the ileum. In response to a chronic low-P(i) diet, there is an adaptive response restricted to the jejunum, with increased brush border membrane (BBM) Na-P(i) transport activity and NaPi-2b, but not PiT-1, protein and mRNA abundance. However, in rats acutely switched from a low- to a high-P(i) diet, there is an increase in BBM Na-P(i) transport activity in the duodenum that is associated with an increase in BBM NaPi-2b protein abundance. Acute adaptive upregulation is restricted to the duodenum and induces an increase in serum P(i) that produces a transient postprandial hyperphosphatemia. Our study, therefore, indicates that Na-P(i) transport activity and NaPi-2b protein expression are differentially regulated in the duodenum vs. the jejunum and that postprandial upregulation of NaPi-2b could be a potential target for treatment of hyperphosphatemia.

Modulation of apical Na+/Pi cotransporter type IIb expression in epithelial cells of goat mammary glands

Recently, the type II sodium-dependent phosphate cotransporter NaPi IIb, which mediates the intestinal phosphate transport, was detected in the apical membranes of caprine mammary gland epithelial cells. Regulatory influences of developmental stages, dietary phosphorus (P) supply and hormones like calcitriol are well described for the intestinal NaPi IIb. Therefore, it was the aim of this study to examine the influence of involution and dietary P restriction on the expression of mammary gland NaPi IIb and of vitamin D receptor (VDR). During involution both, NaPi IIb and VDR, showed an initial increase of expression. This resulted in a delayed response on protein level. Dietary P restriction resulted in a decrease of mRNA expression which was not reflected on protein level. Influenced expression pattern, at least on mRNA level, indicate that mammary gland NaPi IIb is a regulated phosphate transporter which might have an important role especially during involution. Coexpression pattern with VDR provides an indication that calcitriol could be the modulator of these adaptive responses to involution and dietary P restriction. Therefore, a physiological meaning of NaPi IIb in mammary gland epithelia during processes of cell regeneration has to be considered.

Regulation of the rat intestinal phosphate transporters by dietary phosphate

Elevated serum phosphate (Pi) remains a clinical challenge in patients with chronic kidney disease. However, Pi absorption mechanism in the small intestine is not fully understood. NaPi‐2b was identified as the main transporter responsible for intestinal Pi absorption. In mice NaPi‐2b expression concentrates mainly in the ileum. In contrast, rat NaPi‐2b mRNA and protein is expressed in jejunum and duodenum with negligible amounts in ileum, a pattern similar to humans. We report expression of another NaPi transporter showing a similar expression profile: Pit‐1. We characterized intestinal NaPi transport regulation by dietary Pi during chronic and acute alterations in dietary Pi. Chronic low Pi diet induces an increase in jejunal NaPi transport activity and increases in BBM NaPi‐2b protein and mRNA abundance. In contrast, we found an unexpected regulatory response in rats switched from a chronic low Pi diet to a high Pi diet acutely: Duodenum BBM NaPi uptake and NaPi‐2b protein is highly up‐regulated. Moreover, under this acute condition serum Pi is markedly increased as early as 2 hours after feeding. We propose that increased transcellular Pi transport mediated by NaPi‐2b is inducing the unfavorable increase of serum Pi under this condition. Moreover, Pit‐1expression in this tissue could also be playing a role in the intestinal Pi absorption in rats.

Identification of intestinal phosphate transporters in fishes and shellfishes

Phosphorus (P) excreted from aquaculture systems pollutes aquatic environment. Reducing P output requires reducing P input in the feeds. Reducing P in feeds, however, increases the risk of P deficiency in fish. Thus, diagnosis of P deficiency in fish will be important to avoid chronic P deficiency. To detect incipient P deficiency, a sensitive method is needed. Previously, in trout, inorganic P transporters (NaPi) in the intestine have been shown to respond rapidly to early P deficiency. For other fishes, however, little is known about the NaPi sequences, not to mention their dietary responses. In this study, intestinal NaPi sequences were isolated anew in 23 fish species, including major aquaculture species. Also, NaPi-like sequences were isolated from three molluscan species. Phylogenetic analysis of the NaPi sequences showed reasonable agreement with known evolutionary relationships. Tissue distribution of NaPi messenger RNA (mRNA) was studied in rainbow trout, crucian carp, and tilapia by real-time reverse-transcription polymerase chain reaction (RT-PCR), which revealed distribution of NaPi mRNA in several tissues other than the intestine. Acute, but not chronic, dietary P restriction increased (P = 0.01) NaPi mRNA abundance by twofold in crucian carp intestine.

Regulation of the rat intestinal phosphate transporter NaPi‐2b by dietary phosphate

Elevated serum phosphate (Pi) remains a clinical challenge in patients with chronic kidney diseases. Pi homeostasis is determined by intestinal absorption and renal excretion. Intestinal Pi absorption is mediated by sodium‐dependent Pi uptake across the apical membrane of enterocytes by the NaPi‐2b transporter. Studies in mice have shown expression of NaPi‐2b mainly in the ileum. In contrast, in rats absorption of Pi occurs in the duodenum and jejunum, but not in ileum, a pattern similar to humans. Protein studies in rats have been not possible because of a lack of suitable antibodies. We report here the use of a specific antibody used successfully in rats for the study of the regulation of NaPi‐2b. We found that NaPi‐2b transporter mRNA and protein is mainly expressed in jejunum, with lower levels in duodenum and negligible amounts in ileum. NaPi‐2b expression as well as Na‐dependent Pi uptake was increased in rats adapted to a chronic low Pi diet (0.1% Pi) both in duodenum and jejunum. All these results were confirmed by immunofluorescence microscopy in intestinal sections. In addition, we studied mRNA expression of the type III NaPi transporters: Pit‐1 is highly expressed in all three segments and Pit‐1 mRNA is regulated by dietary Pi. In conclusion, regulation of intestinal Pi transport and NaPi‐2b by dietary Pi in rats is concentrated at duodenum and jejunum sections. This research was supported by NIH and AHA.

Stimulation of the intestinal phosphate transporter SLC34A2 by the protein kinase mTOR

Adequate phosphate homeostasis is of critical importance for a wide variety of functions including bone mineralization and energy metabolism. Phosphate balance is a function of intestinal absorption and renal elimination, which are both under tight hormonal control. Intestinal phosphate absorption is accomplished by the Na +, phosphate cotransporter NaPi IIb (SLC34A2). Signaling mechanisms mediating hormonal regulation of SLC34A2 are incompletely understood. The mammalian target of rapamycin (mTOR) is a kinase regulating a variety of nutrient transporters. The present experiments explored whether mTOR regulates the activity of SLC34A2. In Xenopus oocytes expressing SLC34A2 but not in water injected oocytes phosphate (1 mM) induced a current (Ip) which was significantly enhanced by coexpression of mTOR. Preincubation of the oocytes for 24 h with rapamycin (50 nM) did not significantly affect Ip in the absence of mTOR but virtually abolished the increase of Ip following coexpression of mTOR. The wild type serum and glucocorticoid inducible kinase SGK1 and the constitutively active S422DSGK1 similarly stimulated Ip, an effect again reversed by rapamycin. Coexpression of the inactive mutant of the serum and glucocorticoid inducible kinase K119NSGK1 significantly decreased Ip and abrogated the stimulating effect of mTOR on Ip. In conclusion, mTOR and SGK1 cooperate in the stimulation of the intestinal phosphate transporter SLC34A2.

Intestinal phosphate absorption and the effect of vitamin D: a comparison of rats with mice

Previously, it was thought that intestinal phosphate transport occurred exclusively in the proximal small intestine of rodents and humans. However, a recent study has demonstrated that the ileum of mice contributes significantly to the absorption of dietary phosphate, but it is not known whether this region is also an important site of phosphate absorption in the rat. In the present study, we have investigated the mRNA and protein levels of the sodium-phosphate cotransporter, NaPi-IIb, in three regions of rat and mouse small intestine, and related its expression levels to the rate of net phosphate absorption, as measured using the in situ intestinal loop technique. 1,25-Dihydroxyvitamin D3 is an important physiological regulator of intestinal phosphate absorption that increases phosphate transport in both the duodenum and jejunum of the rat. Based on the recently proposed regional profile of phosphate absorption along the mouse small intestine, we have re-evaluated the effects of 1,25-dihydroxyvitamin D3 using three distinct regions of the mouse and rat small intestine. Our studies have revealed important differences in the intestinal handling of phosphate between mice and rats. In mice, maximal phosphate absorption occurs in the ileum, which is paralleled by the highest expression levels of NaPi-IIb mRNA and protein. In contrast, in rats maximal absorption occurs in the duodenum with very little absorption occurring in the ileum, which is similar to the pattern reported in humans. However, in both rodent species only the jejunum shows an increase in phosphate absorption in response to treatment with 1,25-dihydroxyvitamin D3.

Clinical approach to clarifying the mechanism of abnormal bone metabolism in McCune–Albright syndrome

Recent advances in our knowledge of the abnormal bone metabolism associated with McCune-Albright syndrome (MAS) is briefly reviewed. Polyostotic fibrous bone dysplasia and hypophosphatemia are well-known characteristics of MAS. To clarify the mechanism of bone dysplasia, an approach that uses human cells isolated from MAS patients was important. It is now clear that normal skeletal stromal cells without mutation of the Gsalpha protein are necessary for the presence of bone dysplasia and that exaggerated production of interleukin-6 by fibrous bone cells with mutation of the Gsalpha protein is linked to the increased number of osteoclasts in bone tissues. The observation of increased bone resorption by the increased osteoclasts is one of the reasons for using bisphosphonates to treat the bone lesions of MAS. The key observation of the mechanism of hypophosphatemia in MAS was in a clinical report, which suggested that the presence of some humoral factors regulate phosphate metabolism. Recently, the humoral factor that causes hypophosphatemia in MAS was clarified to be fibroblast-growth factor 23 (FGF-23), although the possibility of some other humoral factors was not excluded. This is because a humoral factor inhibiting intestinal phosphate transport is present in culture medium obtained from the cells derived from fibrous bone dysplasia. The abnormal vitamin D mechanism in response to hypophosphatemia in MAS patients also proved recently to be caused by the increased circulating FGF-23 levels. The lines of evidence described suggest that FGF-23 and other factors may coexist, causing hyperphosphaturia and impaired intestinal absorption of phosphate, respectively.

Inhibitory effect of JTP-59557, a new triazole derivative, on intestinal phosphate transport in vitro and in vivo

JTP-59557 [(−)-4-(2- tert-Butyl-4,5-dichlorophenyl)-5-(5-trifluoromethylpyridin-2-ylsulfanyl)-4H-[1,2,4]triazol-3-ol] showed an inhibitory effect on Na +-dependent inorganic phosphate (Pi) transport in intestinal brush border membrane vesicles with an IC 50 value of 0.40 μM in rabbit and with an IC 50 of 0.19 μM in rat, without affecting Na +-independent Pi and Na +-dependent d-glucose transport activities. In Chinese hamster ovary (CHO) cells expressing human type IIb Na/Pi cotransporter (type IIb), JTP-59557 decreased human type IIb-mediated Pi uptake with an IC 50 of 0.12 μM. In rabbit intestinal brush border membrane vesicles, JTP-59557 behaved as a noncompetitive inhibitor with respect to Pi. In an in vivo study, single administration of JTP-59557 significantly decreased the intestinal Pi absorption rate, when either Pi solution or laboratory chow was given to rats. In this report, we show that JTP-59557 is a potent, selective, stereospecific, noncompetitive inhibitor of intestinal Na/Pi cotransporters including type IIb, and it may represent a new class of intestinal Pi absorption inhibitor.

Nicotinamide prevents the development of hyperphosphataemia by suppressing intestinal sodium-dependent phosphate transporter in rats with adenine-induced renal failure

Nicotinamide has been shown to inhibit intestinal sodium-dependent phosphate transport activity in normal rats. It was reported recently that type IIb sodium-dependent phosphate co-transporter (NaPi-2b) is a carrier of intestinal phosphate absorption, and that its expression level is regulated by serum 1,25-dihydroxyvitamin D [1,25(OH)(2)D] and Pi levels in normal rats. However, in chronic renal failure (CRF), serum 1,25(OH)(2)D and Pi levels are often abnormal. In a rat model of CRF, we investigated whether short-term nicotinamide administration was effective in reducing intestinal phosphate absorption and, if so, whether the effect was mediated by intestinal NaPi-2b. Adenine-induced CRF rats were given a single daily intrapenitoneal administration of nicotinamide or vehicle solution for 6 days, and time course changes in serum Pi, Ca, blood urea nitrogen (BUN) and creatinine levels were monitored. Intestinal phosphate absorption was examined by oral administration of radiolabelled phosphate on the final day. In addition, NaPi-2b protein content in jejunum brush border membranes was determined. Nicotinamide prevented the progressive increase in serum Pi associated with renal failure and significantly inhibited intestinal Pi absorption as assessed by the influx of orally administered radiolabelled phosphate into the circulation. This effect was accompanied by a decrease in NaPi-2b expression in jejunum brush border membranes. In addition, nicotinamide treatment was also associated with less marked elevations in BUN and serum creatinine and a higher creatinine clearance. Nicotinamide inhibited intestinal Pi absorption in a rat model of CRF, at least in part by inhibiting the expression of NaPi-2b, and appeared to protect against the deterioration of renal function.