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.

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Absorption of Inorganic Phosphate in the Human Small Intestine

Clinical Science ◽

10.1042/cs0560407 ◽

1979 ◽

Vol 56 (5) ◽

pp. 407-412 ◽

Cited By ~ 47

Author(s):

J. Walton ◽

T. K. Gray

Keyword(s):

Small Intestine ◽

Inorganic Phosphate ◽

Water Movement ◽

Human Subjects ◽

Sodium Concentration ◽

Phosphate Concentration ◽

Phosphate Absorption ◽

Human Small Intestine ◽

Intestinal Phosphate Absorption

1. Intestinal phosphate absorption in human subjects was studied by the technique of triple lumen intestinal perfusion in vivo. 2. Ileal phosphate absorption increased as the intraluminal phosphate concentration was increased. 3. Ileal rates of phosphate absorption were lower at any given intraluminal phosphate concentration than previously described jejunal rates. Acidification of the ileal lumen did not increase phosphate absorption. 4. Phosphate absorption was shown in the jejunum to be dependent on the intraluminal sodium concentration. 5. Phosphate absorption in the human small intestine consists of at least two components, one directly proportional to water movement and the second apparently independent of water movement.

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Tumor necrosis factor-alpha impairs intestinal phosphate absorption in colitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90722.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. G775-G781 ◽

Cited By ~ 19

Author(s):

Huacong Chen ◽

Hua Xu ◽

Jiali Dong ◽

Jing Li ◽

Fayez K. Ghishan

Keyword(s):

Egf Receptor ◽

Phosphate Transport ◽

Luciferase Assay ◽

Receptor Interaction ◽

Mobility Shift ◽

Necrosis Factor Alpha ◽

Bone Disorders ◽

Phosphate Absorption ◽

Tnf Α ◽

Intestinal Phosphate Absorption

Phosphate homeostasis is critical for many physiological functions. Up to 85% of phosphate is stored in bone and teeth. The remaining 15% is distributed in cells. Phosphate absorption across the brush-border membrane (BBM) of enterocytes occurs mainly via a sodium-dependent pathway, which is mediated by type IIb sodium-phosphate cotransporters (NaPi-IIb). Patients of inflammatory bowel diseases (IBDs) suffer not only from diarrhea and nutrient malabsorption but also from bone loss. About 31–59% of patients with IBD develop bone disorders. Since the intestine is a primary location for dietary phosphate absorption, it is logical to postulate that there is an inverse relationship between gastrointestinal disorders and phosphate transport, which, in turn, contributes to bone disorders observed in patients with IBD. Phosphate absorption and NaPi-IIb expression was studied with BBM vesicles isolated from trinitrobenzene sulphonic acid (TNBS) animals as well as in Caco-2 cells. The mechanism of TNF-α downregulation of NaPi-IIb expression was investigated by luciferase assay, gel mobility shift assay (GMSA), and coimmunoprecipitation. Intestinal phosphate absorption mediated by NaPi-IIb was reduced both in TNBS colitis and in TNF-α-treated cells. Transient transfection indicated that TNF-α inhibits NaPi-IIb expression by reducing NaPi-IIb basal promoter activity. GMSAs identified NF1 protein as an important factor in TNF-α-mediated NaPi-IIb downregulation. Signaling transduction study and coimmunoprecipitation suggested that TNF-α interacts with EGF receptor to activate ERK1/2 pathway. Intestinal phosphate absorption mediated by NaPi-IIb protein is reduced in colitis. This inhibition is mediated by the proinflammatory cytokine TNF-α through a novel molecular mechanism involving TNF-α/EGF receptor interaction.

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Effects of insulin and glucose on renal phosphate reabsorption: interactions with dietary phosphate.

Journal of the American Society of Nephrology ◽

10.1681/asn.v2111593 ◽

1992 ◽

Vol 2 (11) ◽

pp. 1593-1600

Author(s):

M Allon

Keyword(s):

Phosphate Uptake ◽

Membrane Vesicles ◽

Phosphate Transport ◽

Tubular Reabsorption ◽

Insulin Deficiency ◽

Renal Brush Border Membrane ◽

Renal Phosphate Reabsorption ◽

Catabolic State ◽

Dietary Phosphate ◽

Phosphate Depletion

Both insulin deficiency and glycosuria are known to inhibit the tubular reabsorption of phosphate. This inhibition has previously been evaluated either in the fasted state or on a normal phosphate diet. The goal of this study was to evaluate how dietary phosphate depletion affected the relative effects of insulin deficiency and glycosuria on the tubular reabsorption of phosphate. Rats were maintained on either a low- (0.03%) or normal (0.8%) phosphate diet. After 5 days, one half of the animals in each group received streptozotocin to induce short-term insulin deficiency, whereas the other half received vehicle alone. Two days later, sodium-dependent phosphate uptake by renal brush border membrane vesicles (BBMV) was evaluated in each of the four experimental groups. The effect of glucose on phosphate uptake was determined by the addition of varying concentrations of glucose (between 0 and 32 mmol/L) to the extravesicular transport fluid. BBMV phosphate uptake was about threefold higher in the nondiabetic rats fed a low-phosphate diet as compared with the nondiabetic animals maintained on a normal phosphate diet. In rats maintained on a low-phosphate diet, streptozotocin treatment prevented the increase in BBMV phosphate transport; in contrast, in animals fed a normal phosphate diet, streptozotocin treatment had no effect on BBMV phosphate transport. Extravesicular glucose significantly inhibited phosphate transport in a dose-related manner, regardless of dietary phosphate or insulin status. Because fasting mimics the catabolic state associated with insulin deficiency, BBMV phosphate transport was also measured in rats fasted for 48 h after the administration of streptozotocin or vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

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Intestinal phosphate absorption: The paracellular pathway predominates?

Experimental Biology and Medicine ◽

10.1177/1535370219831220 ◽

2019 ◽

Vol 244 (8) ◽

pp. 646-654 ◽

Cited By ~ 2

Author(s):

Matthew Saurette ◽

R Todd Alexander

Keyword(s):

Kidney Disease ◽

Animal Studies ◽

Western Diet ◽

Phosphate Absorption ◽

Sodium Hydrogen ◽

Sodium Hydrogen Exchanger ◽

Gradient Based ◽

Intestinal Phosphate Absorption ◽

Stage Renal Disease ◽

End Stage

Hyperphosphatemia is nearly universal in patients with advanced chronic kidney disease and end stage renal disease. Given the considerable negative sequelae associated with hyperphosphatemia, i.e. increased cardiovascular disease, hastening of renal failure and death, reducing serum phosphate is a goal of therapy. In the absence of sufficient renal function, intestinal phosphate absorption is the remaining target to reduce plasma phosphate levels. Much work has been done with respect to understanding transcellular phosphate absorption. Both animal studies using inducible or intestinal NaPi-2b knockout mice and specific NaPi-2b inhibitors revealed this transporter as the primary mechanism mediating transcellular phosphate absorption in the intestine. However, this has not translated into effective phosphate lowering therapies in patients with kidney disease. More recently, it was observed that inhibition of the epithelial sodium hydrogen exchanger, sodium–hydrogen exchanger isoform 3 (NHE3), or its genetic deletion, decreases intestinal phosphate absorption. The mechanism mediating this effect is through increased transepithelial resistance and reduced paracellular phosphate permeability. Thus, NHE3 inhibition reduces paracellular phosphate permeability in the intestine. The transepithelial potential difference across intestinal epithelium is lumen negative and phosphate commonly exists as a divalent anion. Further, consumption of the typical Western diet provides a large lumen to blood phosphate concentration gradient. Based on these observations we argue herein that the paracellular phosphate absorption route is the predominant pathway mediating intestinal phosphate absorption in humans. Impact statement This review summarizes the work on transcellular intestinal phosphate absorption, arguing why this pathway is not the predominant pathway in humans consuming a “Western” diet. We then highlight the recent evidence which is strongly consistent with paracellular intestinal phosphate absorption mediating the bulk of intestinal phosphate absorption in humans.

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Membrane controls of epithelial phosphate transport

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y87-049 ◽

1987 ◽

Vol 65 (3) ◽

pp. 275-286 ◽

Cited By ~ 13

Author(s):

Gary A. Quamme ◽

R. Jean Shapiro

Keyword(s):

Brush Border ◽

Brush Border Membrane ◽

Basolateral Membrane ◽

Phosphate Transport ◽

Hydrogen Ions ◽

Acid Base Balance ◽

Phosphate Absorption ◽

Renal Epithelium ◽

Sequence Of Events ◽

Sodium Dependent

Phosphate homeostasis involves efficient intestinal absorption of dietary phosphate and sensitive renal conservation of filtered phosphate. Phosphate transport occurs by similar mechanisms across the intestinal and renal epithelium. This includes secondary active uptake across the brush-border membrane, movement of phosphate across the cytosol or into the metabolic phosphate pool, and finally the passive exit from the basolateral membrane. Active transport across the brush-border membrane involves cotransport of phosphate with sodium, which moves down its electrochemical gradient. As this process is the rate-limiting step, it is thought to be the controlling event in intestinal and renal absorption. The interaction of phosphate, sodium, and hydrogen ions with the recognition proteins involved with sodium-dependent phosphate transport is complex and not fully understood. Furthermore, the lipid bilayer structure may play a significant role in controlling the sequence of events in the movement across the brush-border membrane. Transfer of phosphate through the cytosol and exit across the basolateral membrane is less well understood, although the latter transmembrane flux is thought to be carrier mediated. Intestinal phosphate absorption is determined principally by plasma calcium and phosphate concentrations (1,25(OH)2 D3) and dietary availability of phosphate (intrinsic adaptation). On the other hand, renal conservation is determined by the available calcium (PTH), phosphate (intrinsic adaptation), and acid–base balance (hydrogen ions). These controls alter sodium-dependent phosphate cotransport across the brush-border membrane of the epithelial cell. The chemical alterations of the brush-border membrane and the metabolic events leading to changes in the brush-border membrane are not understood. The use of isolated, purified membranes and innovations of current techniques will enhance our understanding of these events and allow us to explain the mechanisms controlling epithelial phosphate absorption.

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Small Intestinal Phosphate Absorption: Novel Therapeutic Implications

American Journal of Nephrology ◽

10.1159/000518110 ◽

2021 ◽

pp. 1-9

Author(s):

Jerry Yee ◽

David Rosenbaum ◽

Jeffrey W. Jacobs ◽

Stuart M. Sprague

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Paracellular Pathway ◽

Phosphate Binders ◽

Phosphate Absorption ◽

Therapeutic Implications ◽

Sodium Hydrogen ◽

Sodium Hydrogen Exchanger ◽

Dietary Phosphate ◽

Intestinal Phosphate Absorption

Background: Chronic kidney disease (CKD) affects approximately 15% of adults in the USA. As CKD progresses, urinary phosphate excretion decreases and results in phosphate retention and, eventually, hyperphosphatemia. As hyperphosphatemia is associated with numerous adverse outcomes, including increased cardiovascular mortality, reduction in phosphorus concentrations is a guideline-recommended, established clinical practice. Dietary phosphate restriction, dialysis, and phosphate binders are currently the only options for phosphate management. However, many patients with hyperphosphatemia have phosphorus concentrations >5.5 mg/dL, despite treatment. Summary: This review presents recent advances in the understanding of intestinal phosphate absorption and therapeutic implications. Dietary phosphate is absorbed in the intestine through two distinct pathways, paracellular absorption and transcellular transport. Recent evidence indicates that the paracellular route accounts for 65–80% of total phosphate absorbed. Thus, the paracellular pathway is the dominant mechanism of phosphate absorption. Tenapanor is a first-in-class, non-phosphate binder that inhibits the sodium-hydrogen exchanger 3 or solute carrier family 9 member 3 (SLC9A3) encoded by the SLC9A3 gene, and blocks paracellular phosphate absorption. Key Messages: Targeted inhibition of sodium-hydrogen exchanger 3 effectively reduces paracellular permeability of phosphate. Novel therapies that target the paracellular pathway may improve phosphate control in chronic kidney disease.

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Effects of metabolic acidosis, alkalosis, and dietary hydrogen ion intake on phosphate transport in the proximal convoluted tubule

AJP Renal Physiology ◽

10.1152/ajprenal.1985.249.5.f769 ◽

1985 ◽

Vol 249 (5) ◽

pp. F769-F779 ◽

Cited By ~ 1

Author(s):

G. A. Quamme

Keyword(s):

Metabolic Acidosis ◽

Ph Value ◽

Phosphate Transport ◽

Hydrogen Ion ◽

Ion Concentration ◽

Hydrogen Ion Concentration ◽

Phosphate Absorption ◽

Phosphate Excretion ◽

Dietary Phosphate ◽

Bicarbonate Infusion

Early proximal convoluted tubules were perfused in vivo with equilibrium Ringer buffered at pH 7.65 and 6.5 to characterize phosphate absorption due to changes in extracellular and intracellular hydrogen ion concentration. Phosphate absorption is normally greater from intraluminal pH 7.65 compared with pH 6.5 in thyroparathyroidectomized rats with fractional phosphate excretion of 0.5%. Metabolic alkalosis produced by bicarbonate infusion in rats ingesting normal amounts of phosphate (45 mg/day) resulted in an increase in overall renal phosphate reabsorption (fractional phosphate excretion 0.3%). The Jmax and Km values were: pH 7.65, 33.67 +/- 13.49 pmol X min-1 X mm-1, and 1.74 +/- 0.30 mM; pH 6.5, 24.87 +/- 6.22 and 0.50 +/- 0.25, respectively. By contrast, rats on a high dietary phosphate intake (180 mg/day) demonstrated a large increase in urinary phosphate excretion (18%) following bicarbonate infusion, which was due to a decrease in tubular phosphate absorption from both alkaline and acidic luminal pH values. Acute metabolic acidosis did not significantly alter tubular transport at either intraluminal pH value. In contrast, rats maintained on an elevated dietary acid intake for 5 days had a phosphaturia (fractional excretion 7.1%) and diminished reabsorptive capacity. Dietary acidosis also decreased tubular phosphate transport in rats previously maintained on phosphate-restricted diets. These data suggest that acid-base balance may modulate tubular phosphate transport independent of intraluminal pH and phosphate concentration. Further, these changes depend on the chronicity of exposure and act independent but integral to the effects of parathyroid hormone and the intrinsic adaptation to dietary phosphate availability.

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Effects of intraluminal pH and dietary phosphate on phosphate transport in the proximal convoluted tubule

AJP Renal Physiology ◽

10.1152/ajprenal.1985.249.5.f759 ◽

1985 ◽

Vol 249 (5) ◽

pp. F759-F768 ◽

Cited By ~ 1

Author(s):

G. A. Quamme ◽

C. L. Mizgala ◽

N. L. Wong ◽

S. J. Whiting

Keyword(s):

Ph Value ◽

Basolateral Membrane ◽

Plasma Concentrations ◽

Phosphate Transport ◽

Proximal Tubule Cell ◽

Phosphate Absorption ◽

Saturation Kinetics ◽

Dietary Phosphate ◽

Phosphate Exchange ◽

Convoluted Tubules

The proximal tubule cell adjusts its phosphate absorption appropriately to meet the needs of the organism. Studies were performed to characterize some of the cellular changes involved with dietary phosphate adaptation. First, early proximal convoluted tubules were perfused with equilibrium Ringer solutions buffered to pH 7.65 or 6.5. Saturation kinetics for phosphate transport were determined at each pH value. Rats maintained on a diet of normal phosphate composition demonstrated the apparent Jmax and Km parameters about twofold greater with intraluminal pH 7.65 vs. pH 6.5. The Jmax values increased to 53.47 +/- 3.71 and 42.73 +/- 5.48 pmol X min-1 X mm-1, respectively, when the rats were placed on a phosphate-restricted diet for 5 days. By contrast, adaptation to a high dietary phosphate content resulted in diminished phosphate absorption, 8.53 +/- 1.80 and 12.87 +/- 1.61 pmol X min-1 X mm-1, for the respective pH 7.65 and 6.5 values. Second, the effect of peritubule phosphate concentration was evaluated at constant intraluminal phosphate concentrations. Unidirectional lumen-to-blood phosphate efflux was inhibited at all plasma phosphate concentrations in animals maintained on normal dietary phosphate. By contrast, rats adapted to a low phosphate diet exhibited an increase in phosphate absorption: pH 7.65, 86.21 +/- 2.63, and pH 6.5, 140.84 +/- 86.76 pmol X min-1 X mm-1 when plasma concentrations were elevated two- or three-fold from 2.4 to 6.4 mM. This was attributed to enhanced phosphate exchange on the basolateral membrane. Further hyperphosphatemic levels, above 6.4 mM, inhibited phosphate absorption. These data suggest that net phosphate absorption is determined, in part, by factors other than sodium-dependent uptake of phosphate by the brush border membrane including intracellular pH and peritubular phosphate that act in concert to control renal phosphate absorption.

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