Control of Renal Solute Excretion by Enteric Signals and Mediators
Leslie Thomas* and
Rajiv Kumar*,
* Division of Nephrology and Hypertension, Department of Internal Medicine, and Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota
Correspondence: Dr. Rajiv Kumar, Mayo Clinic, MS 1-120, Rochester, MN 55905. Phone: 507-284-0020; Fax: 507-538-3954; E-mail: rkumar{at}mayo.edu
Renal solute excretion is important for the homeostasis of variousions. It is widely believed that hormones such as aldosterone,parathyroid hormone, the vitamin D endocrine system, and growthfactors are responsible for alterations in renal ion transportin response to increased absorption of enteric solutes. In thecases of sodium, potassium, and phosphorus, moieties producedin the gastrointestinal tract alter renal ion transport whenfoods that have high concentrations of cognate ions are ingested.The gastrointestinal tract senses the presence of increasedluminal concentrations of these ions, presumably via specific"sensors," and responds by releasing effector substances intothe intestinal wall and portal circulation. These substancesrapidly increase renal excretion or reduce renal tubular reabsorptionand thus blunt large increases in the serum concentrations ofthese ions. The characterization of enteric solute sensors andmediators will greatly advance our understanding of physiologicmechanisms that control solute homeostasis and will allow thedevelopment of specific drugs that stimulate or inhibit thesepathways.
The renal response to ingested solutes and the regulation ofnutrient and solute balance are vital for the well-being ofan organism. Foods that contain protein, carbohydrate, and fatare processed to amino acids, monosaccharides, and fatty acidsand triglycerides. These substances and electrolytes and mineralsare absorbed with varying degrees of efficiency in the intestine,often in response to the perceived needs of the organism. Insome instances, the amount of the nutrient absorbed in the intestinedepends on the amount present in the diet, and with large influxesof nutrient materials into the extracellular fluid, it fallsto the kidney to remove the excessive amounts absorbed by theintestine from the serum and extracellular fluid, either byincreasing the amount excreted by tubular processes or by reducingthe amount reabsorbed in the tubule after glomerular filtration.
It is widely believed that the renal response to ingested solutesis regulated by hormones such as aldosterone, in the case ofsodium and potassium, and parathyroid hormone and the vitaminD endocrine system, in the case of calcium and phosphate. New(and old) information also suggests that factors produced inthe gastrointestinal tract are released after changes in intestinalluminal solute concentrations and mediate changes in renal solutetransport. This "enteric–renal solute–transportingregulating axis" represents an underappreciated mechanism bywhich renal solute transport is regulated.
Dietary sodium induces a more marked natriuresis than intravenoussodium. The regulation of renal excretory or reabsorptive processesexclusively depends on the activity of various hormones or localrenal factors, the synthesis or release of which depends onalterations in the serum or extracellular fluid concentrationsof the various ions. Decreases in renal sodium excretion inresponse to a low-salt diet depend on changes in aldosteronesynthesis.1 Indeed, a lack of aldosterone synthesis is responsiblefor many of the manifestations of Addison's disease. The roleof aldosterone (and inhibition of its synthesis) in increasingsalt excretion is less clearly defined when a high-salt dietis ingested. Data suggest that other factors play a role inthis process and that the role of aldosterone is minimal inthe adaptation to high-sodium meals. Carey and others2–4have demonstrated that salt-depleted individuals who were givenoral sodium chloride excreted much more sodium in their urinethan did individuals who were given the same amount of sodiumchloride intravenously. Plasma aldosterone concentrations werethe same whether the sodium load was given orally or intravenously.In addition, patients with documented hypoaldosteronism alsoexcreted more sodium in the urine when a sodium chloride loadwas given orally than when sodium was given intravenously. Thisconclusively demonstrates that the exaggerated response to oralsodium chloride loading is independent of aldosterone.2 Carey2suggested the data also indicate "the presence of a splanchnicinput monitor for sodium which partially regulates renal sodiumexcretion and is not dependent upon a turn-off mechanism forsodium excretion." By implication, an effector substance ormechanism to signal the kidney to increase its capacity to increasesodium excretion must exist. Previous work demonstrated thatthe liver may contain substances that induce a natriuresis whenadministered intravenously.5 Guanylin and uroguanylin may fulfillthe role of just such effector substances.6–10 These smallpeptides increase sodium excretion in the intestine and diminishsodium reabsorption in the proximal tubule by increasing guanylatecyclase activity in these cells.
There also are gut factors that induce kaliuresis. Similar toenteric factors that influence renal sodium handling, evidencesuggests the presence of gut factors that act independent ofaldosterone to regulate renal potassium excretion. Elevatedserum potassium directly alters potassium excretion by collectingduct cells and thereby promotes kaliuresis.11–13 An elevationin serum potassium concentration also increases aldosteronesynthesis, which, in turn, increases kaliuresis.14 Rabinowitz15–18argued that the increase in serum potassium after a high-potassiummeal is too small (0.5 mEq/L) to initiate either of these adaptiveresponses and that an intestinal signal is responsible for theincrease in renal potassium excretion after a high potassiummeal. Recent, interesting work from Lee et al.13 further strengthenedthis observation. Lee et al. showed that the administrationof potassium by intravenous, intraportal, or intragastric methodhas a similar effect on plasma potassium and renal potassiumexcretion profiles in the fasting state but that the administrationof a low-potassium meal along with intragastric potassium infusionsubstantially reduces the increase in plasma potassium and greatlyenhances renal potassium excretion. These findings suggest thepresence of a gut factor that mediates increased renal potassiumexcretion. Lee et al.13 suggested that this unique enteric factormight be released from the intestine. The factor does not seemto be insulin, and the chemical identity of such a factor hasnot been determined. Their experiments, however, make a persuasivecase for the existence of such a factor.
EVIDENCE FOR AN ENTERIC–RENAL PHOSPHATE–TRANSPORT REGULATING AXIS
The key physiologic roles of the intestine and kidney in phosphatehomeostasis are appreciated by all nephrologists (Figure 1).19,20The regulation of renal phosphate transport by widely knownhormones such as parathyroid hormone (PTH), the vitamin D–endocrinesystem, the phosphatonins (fibroblast growth factor-23 [FGF-23]and secreted frizzled-related protein-4 [sFRP-4]), and the roleof renal phosphate transporters in the kidney and intestinehave been the subjects of recent reviews, and the reader isreferred to them for further information.19,20
Figure 1. Phosphorus homeostasis in humans. Adapted from Berndt and Kumar,19 with permission.
The prevailing concepts regarding the regulation of phosphatehomeostasis, largely based on changes in concentrations of PTHand the vitamin D–endocrine system, are detailed in Figure 2.The roles of PTH and the vitamin D–endocrine system inthe scheme shown are clear. The phosphatonins, to the extentthat they may be physiologic regulators of phosphate homeostasis,are shown to function as regulators of 25-hydroxyvitamin D 1-hydroxylaseactivity.
Figure 2. The PTH–vitamin D endocrine system in hypo- and hyperphosphatemic states. Adapted from Berndt and Kumar,19 with permission.
Several lines of evidence suggest that changes in PTH cannotfully account for the enhancement of renal phosphate excretionthat has been observed after administration of increasing amountsof dietary phosphate. First, feeding normal humans a high-phosphatediet is associated with large changes in the fractional excretionof phosphate (FE Pi) but with only modest increases in the concentrationof circulating PTH (measured every hour throughout a 24-h period)and urinary nephrogenous cAMP and with no decrease in 1,25-dihydroxyvitaminD (Table 1).21,22 This suggests that increases in PTH and changesin 1,25-dihydroxyvitamin D cannot fully account for the increasein urinary phosphate excretion. That PTH is not the sole regulatorof renal phosphate transport is also supported by earlier datafrom Steele et al.,23 who showed that chronically parathyroidectomizedrats were able to respond to changes in dietary phosphate intakewith an appropriate increase in urinary phosphate excretion.
Table 1. Serum calcium, phosphorus, PTH, and 1,25-dihydroxyvitamin D concentrations in men and women fed a high-phosphorus and low-calcium dieta
The role that the phosphatonins FGF-23 and sFRP-4 might playin renal adaptation to changes in dietary phosphate has alsobeen explored. Whereas FGF-23 and sFRP-4 change in rodent modelsin a manner that would be predicted (high-phosphate diet increasescirculating FGF-23 and renal sFRP-4), the changes in humansare quite variable and modest when measured after high- or low-phosphatediets of long duration (days).24–30 Such changes may notfully account for changes in renal phosphate excretion thatoccur after meals. Humans consuming diets containing increasingamounts of phosphate have decreases in FGF-23 concentrationdespite large increases in the FE Pi26; therefore, changes inFGF-23 cannot entirely account for changes in the FE Pi seenafter phosphate feeding.
The intestine may be a phosphate sensor and regulator of renalphosphate transport. To describe better the adaptations to changesin dietary phosphate, we hypothesized that the intestine might"sense" changes in dietary phosphate and elaborate substancesthat influence the renal excretion of phosphate. To investigatethis possibility, we infused phosphate into different segmentsof the bowel to determine whether the infusion elicited changesin renal phosphate excretion.31
When sodium phosphate is infused into the duodenum of fastedrats, there is a rapid increase in the FE Pi (Figure 3). Thisphenomenon is observed within 10 min of the infusion of phosphateinto the duodenum. Serum phosphate concentrations and the GFRdo not change during the experiments, thereby demonstratingthat a change in the filtered load cannot account for the changein FE Pi. The fractional excretion of sodium and calcium isalso not altered appreciably. Peptides that induce phosphaturia,such as PTH, FGF-23, and sFRP-4, are unchanged. Furthermore,the increase in FE Pi after the intestinal infusion of phosphateoccurs in parathyroidectomized rats in an equally efficientand rapid manner, showing that PTH is not the mediator of thisresponse. Earlier, Martin et al.32 showed the intestinal administrationof phosphate to rats is associated with a rapid increase inPTH concentrations that would likely induce a phosphaturic response.The amount of phosphate administered was greater than in ourexperiments. A PTH-independent mechanism was not investigatedby these investigators.
Figure 3. Evidence for an intestinal mediator of renal phosphate excretion. Mean FE Pi in intact or thyro-parathyroidectomized (TPTX) rats after the intestinal administration of sodium phosphate or sodium chloride. Groups of rats were administered either sodium phosphate or sodium chloride, and FE Pi was measured at 0, 5, 10, 20, and 30 min after commencement of the infusion. •, intact rats given intestinal sodium phosphate; , intact rats given intestinal sodium chloride; , TPTX rats given intestinal sodium phosphate; , TPTX rats given intestinal sodium chloride. Adapted from Berndt et al.,31 with permission.
There is no change in FE Pi when an equivalent amount of sodiumchloride was infused in to the duodenum, thereby showing thatthe process is specific for the phosphate ion. It is interestingthat when sodium phosphate is infused into the stomach of ratsin which the gastric outlet had been ligated, no increase inFE Pi is observed, suggesting that luminal phosphate concentrationsare not sensed in the stomach.
These data suggest that duodenum or some part of the intestinedistal to the duodenum is able to sense phosphate in the lumenof the bowel. The precise nature of this sensor is not known.Whether phosphate uptake into intestinal cells is a prerequisitefor this sensing mechanism is uncertain. It is plausible thata cell-surface phosphate sensor is involved in sensing changesin luminal phosphate concentrations. Receptors on the surfaceof cells are involved in sensing small molecules on variousparts of the tongue and within the gastrointestinal tract.33,34G-protein–coupled taste receptors for sweet, bitter, andumami flavors are distributed on the surface of the tongue,and nutrient sensors resembling taste receptors are also foundon the surface of enteroendocrine and other cells are presentthroughout the gastrointestinal tract.33,34 The calcium-sensingreceptor, besides detecting calcium, functions as an amino acidsensor.35 The calcium-sensing receptor is present in gastricG cells and acid-secreting parietal cells of the stomach, whereit could play a role in regulating acid secretion in that organin response to meal-induced changes in luminal amino acid concentrations.35The calcium-sensing receptor is also present in the intestineand colon, where it might influence the movement of ions suchas sodium and chloride.36–38 Whether any G-protein–coupledreceptors are involved in sensing alterations in phosphate inthe intestine is unknown.
What triggers the phosphaturic response in the kidney? Neuralcircuits might potentially be involved. Activation of vagal,spinal, and myenteric nerves in the intestinal wall could relaya neural signal centrally, and subsequently modulate renal nerveactivity to reduce phosphate reabsorption. To address this possibility,we instilled phosphate into the duodenum of rats that had undergonea unilateral renal denervation. Denervation did not alter thephosphaturic response to phosphate instillation into the duodenum,thereby demonstrating that renal nerves are not involved inthis process.
The intestine might also elaborate substances that alter renalphosphate reabsorption. To test this possibility, we administeredextracts of the duodenum to rats intravenously. These extractsinduced phosphaturia in rats, showing that the intestine, itself,is the source of a phosphaturic substance that is released uponphosphate infusion into the intestine. The cell type elaboratingsuch a substance is unknown. The intestine is rich in enteroendocrinecells that elaborate various hormones.33,34,39 Examples includethe incretin peptides (glucose-dependent insulinotropic peptide,glucagon-like peptide-1), glucagon-like peptide-2, oxyntomodulin,cholecystokinin, gastrin, and other factors.33,34,39 In addition,intestinal absorptive cells produce factors such as apolipoproteinA IV that modulate satiety.33,34,39 The source of the phosphaturicsubstance may be any one of these cells or some other cell typefound in the intestinal wall. Efforts to identify the chemicalidentity of this factor are under way.
What is an integrated view of the regulation of phosphate homeostasis?Phosphate homeostasis can be thought of in terms of processesthat regulate phosphate over the short and long term (Figure 4).Both of these processes play a role in phosphate homeostasis,but the short-term processes are probably more important inthe postcibal regulation of concentrations of this ion. Short-termprocesses involve the rapid postcibal increase in renal phosphateexcretion by the kidney and are likely to be mediated by novelintestinal factors—"intestinal phosphatonins"—thechemical nature of which remains to be determined. These factors,released soon after meals high in phosphorus, enter the intestineand reset (lower) the tubular maximum for phosphate such thatincreases in serum phosphate levels that occur after a mealare reduced rapidly and large excursions in serum phosphateafter a meal do not occur. In the long term, hormones such asparathyroid hormone and 1,25-dihydroxyvitamin D play a rolein modulating phosphate homeostasis, although their role maybe mainly to change the basal tubular maximum for phosphatein circumstances of high or low phosphate intakes. The postcibalchanges in renal phosphate handling mediated by enteric factorsstill occur as noted previously.
Figure 4. Short- and long-term adaptations to dietary Pi in the kidney. After a meal, FE Pi increases as a result of release of factors from the intestine that reduce reabsorption of phosphate in the proximal tubule. Long-term increases or decreases in dietary Pi are associated with changes in PTH, the vitamin D endocrine system, and possibly the phosphatonins and the concomitant increases or decreases in baseline FE Pi. Postcibal changes in FE Pi continue as before on an altered baseline FE Pi.
What is the relevance of the enteric–renal solute–transportregulating axis? The physiologic relevance of this axis is clearnot just because it better explains observations relevant tophosphate homeostasis but because relevant sensors and mediatorsalso represent targets for drugs that can be used to treat hyperphosphatemiaseen in renal failure. Thus, one might speculate that the FEPi could be increased in early renal failure by "turning on"the sensor for phosphate with a nonabsorbed molecule. The netresult would be a decrease in phosphate retention and concomitanthyperparathyroidism. Alternatively, if an intestinal effectormolecule could be chemically characterized and synthesized,then administration in early renal failure could reduce hyperphosphatemiaafter ingestion of meals containing phosphate. Finally, it isconceivable that an intestinal mediator might reduce intestinalphosphate absorption by preventing postcibal hyperphosphatemia.These concepts could be extended to other ions such as sodiumand potassium as well.
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Top
Abstract
Introduction
-hydroxylase activity. 
, intact rats given intestinal sodium chloride; 
, TPTX rats given intestinal sodium phosphate; 
, TPTX rats given intestinal sodium chloride. Adapted from Berndt et al.,