Summarize the effect of humoral and dietary factors on phosphorus levels.
19 Comments
Muhammad Soobadar
Maintenance of serum phosphate within the normal range depends on a complex interplay between absorption of phosphate in the gut, exchange with bone stores, shifts between intracellular and ECF
Dietary or hormonal changes result in insertion or removal of NaPit2 from the brush border membrane of PCT, which may be rapid (min-hrs) in NaPit2a or slow (hrs-days) in NaPit2c.
NaPit2a is rapidly down-regulated by {high dietary Pi, PTH, FGF23, glucocorticoids, dopamine, estrogen, acute HTN}. NaPit2c is slowly Down-regulated by {high dietary Pi, PTH, FGF23}. With resultant reduced PCT Pi reabsorption.
NaPit2a is up-regulated by {Pi restricted diet, vitamin D3, thyroid hormones}. NaPit2c is up-regulated by {Pi restricted diet, vitamin D3}. With resultant increased PCT Pi reabsorption.
Factors Increase phosphate absorption
Low-PO4 diet, Hyperthyroidism, Active vit D Factors Decrease phosphate absorption
PTH, FGF-23, Acidosis, HTN, high dietary PO4, Glucocorticoids
ingestion of phosphorus-containing foods leads to removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, thereby decreasing phosphate reabsorption from the ultrafiltrate and the opp
Potassium deficiency leads to an increase in phosphate excretion .Potassium deficiency leads to changes in the brush border
membrane lipid composition that are thought to inhibit Npt2a activity
PTH causes decreased renal reabsorption of phosphate and phosphaturia by decreasing the abundance of Npt2a ( within minute ) Npt2c, and PiT-2 ( within hours ) in the renal proximal tubule brush border membrane
A low-fosfat diet increases the absorption of available phosphor from the intestines. On the other hand diet rich in phosphorous decreases absorption.
Thyroid hormone and active vitamin D increase the Pi absorption. This favours hyperphosphatemia.
PTH decreases Pi absorption and exerts phpaturic effect on the kidney. This is usually by reducing the abundance of Npt2a, Npt2c and PiT in the proximal renal tubule.
FGF-23: phosphaturic hormone, increases when Pi is increasing, synthesized by osteoblast and requires Klotho (synthesized in the kidney) for action
–FGF-23 reduces the expression and activity of Na-P cotransporters in PCT
–Thought to decrease the activity of intestinal Na-Pi cotransporters.
— decrease levels of calcitriol by decreasing expression of 1 alpha-hydroxylase
1,25 (OH)2 vştamin D: thought to increase reabsorption by PCT.
The kidneys are the major regulators of Pi homeostasis, Dietary or hormonal changes result in insertion or removal of NaPit2 from the brush border membrane of PCT, which may be rapid (min-hrs) in NaPit2a or slow (hrs-days) in NaPit2c.
NaPit2a is rapidly down-regulated by {high dietary Pi, PTH, FGF23, glucocorticoids, dopamine, estrogen, acute HTN}. NaPit2c is slowly Down-regulated by {high dietary Pi, PTH, FGF23}. With resultant reduced PCT Pi reabsorption.
NaPit2a is up-regulated by {Pi restricted diet, vitamin D3, thyroid hormones}. NaPit2c is up-regulated by {Pi restricted diet, vitamin D3}. With resultant increased PCT Pi reabsorption.
Dietary phosphorus: High phosphate diet -> down regulation of PCT NaPit2a,c -> decreased phosphate reabsorption. Pi restriction causes increased phosphate reabsorption
Hypokalemia leads to confirmational changes in brush border of PCT-> reduced NaPit2a,c activity inspite abundance-> reduced Pi reabsorption.
PTH: phosphaturic hormone-> down regulation of PCT NaPit2a (within minutes) & NaPit2c (within hrs)-> decreased phosphate reabsorption.
FGF23 (phosphaturic)-> down regulation of
NaPit2b -> decreased Intestinal phosphate absorption. Also inhibits 1alphahydroxylase decreases vitamin D activation decreasing Pi absorption and reabsorption.
1,25 OH D: increases intestinal Pi absorption and PCT reabsorption.
Glucocorticoids: increased Glucocorticoid level leads to confirmational changes in brush border of PCT, also it down regulates PCT NaPit2a -> decreased PCT phosphate reabsorption
Dietary Factors Regulating Renal Phosphate Handling:
ingestion of phosphorus-containing foods leads to decreasing phosphate reabsorption from the ultrafiltrate. By contrast, dietary Pi restriction leads to increasing phosphate reabsorption.
Potassium deficiency leads to an increase in phosphate excretion in the urine. Potassium deficiency leads to changes in the brush border membrane lipid composition that are thought to inhibit Npt2a activity.
Hormonal and Other Factors Regulating Renal Phosphate:
PTH causes decreased renal reabsorption of phosphate and phosphaturia.
Fibroblast growth factor23 (FGF23) is produced in osteoblasts in response to increases in serum Pi. To exert its physiologic effects on the proximal tubule, FGF23 requires the presence of a cofactor, Klotho, which is produced in the kidney and activates FGF receptor 1. FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter. FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1ahydroxylase, which is the rate-limiting step in calcitriol synthesis, and increasing renal expression of 24-hydroxylase, which is required for calcitriol degradation. In addition, FGF23 suppresses PTH synthesis, although the parathyroid glands are believed to become resistant to FGF23 as kidney disease progresses.
1,25(OH)2D. Calcitriol is believed to increase phosph reabsorption in the proximal tubule but the effects are confounded by the fact that changes in 1,25(OH)2Dalso alter plasma calcium and PTH levels.
Glucocorticoids. Increased glucocorticoid levels lead to decreased proximal tubule synthesis and abundance of Npt2a as well as changes in brush border membrane lipid composition, which is thought to modulate sodium phosphate cotransporter activity. Estrogen causes phosphaturia by decreasing
the abundance of Npt2a in the proximal tubule without altering Npt2c levels.
Thyroid Hormone increase phosphate absorption by increasing proximal tubule transcription and expression of Npt2a.
Dopamine leads to phosphaturia by inducing internalization of Npt2a from the proximal tubule brush border membrane. Dopamine-mediated internalization of Npt2a is dependent on a scaffolding protein (sodium-hydrogen exchanger regulatory factor 1) Metabolic acidosis stimulates phosphaturia, which helps remove acid from the blood because phosphate serves as a titratable acid metabolic alkalosis increases renal phosphate absorption .
Summarize the effect of humoral and dietary factors on phosphorus levels.Dietary factors regulating renal phosphate handling:
In animals with normal renal function, ingestion ofphosphorus-containing foods leads to removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, thereby decreasing phosphate reabsorption from the ultrafiltrate. By contrast, dietary Pi restriction leads to insertion of the sodium phosphate cotransporters in the proximal tubule brush border membrane, increasing phosphate reabsorption. Potassium deficiency leads to an increase in phosphate excretion in the urine despite a paradoxical increase in the abundance of Npt2a in the proximal tubule brush border membrane that should increase phosphate reabsorption. Potassium deficiency leads to changes in the brush border membrane lipid composition that are thought to inhibit Npt2a activity
Hormonal and Other Factors Regulating Renal Phosphate Handling:
PTH . PTH causes decreased renal reabsorption of phosphate and phosphaturia by decreasing the abundance ofNpt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane .Fibroblast Growth Factor-23. Fibroblast growth factor-23 (FGF23) is produced in osteoblasts in response to increases in serum Pi.FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter
1,25(OH)2D. Calcitriol is believed to increase phosphatereabsorption in the proximal tubule , but the effects areconfounded by the fact that changes in 1,25(OH)2D also alter plasma calcium and PTH levels.
Glucocorticoids Increased glucocorticoid levels lead to decreased proximal tubule synthesis and abundance of Npt2a as well as changes in brush border membrane lipid composition, which is thought to modulate sodium phosphate cotransporter activity
Estrogen.Estrogen causes phosphaturia by decreasing the abundance of Npt2a in the proximal tubule without altering Npt2c levels . Estrogen also increases FGF23 synthesis
Thyroid HormoneIncreased levels of thyroid hormone increase phosphate absorption by increasing proximal tubule transcription and expression of Npt2a . The Npt2a gene contains a thyroid response element and transcription of Npt2a mRNA is regulated by 3,5,3-triiodothyronine
Dopamine. Dopamine leads to phosphaturia by inducing internalization of Npt2a from the proximal tubule brush border membrane
Metabolic AcidosisMetabolic acidosis stimulates phosphaturia, which helps remove acid from the blood because phosphate serves as a titratable acid
HypertensionAn acute increase in BP leads to decreased renal phosphate reabsorption by inducing removal of Npt2a from the proximal tubule brush border membrane microvilli to subapical endosomes
Factors that increase phosphate absorption: Low phosphate diet, 1,25-vitD3, Thyroid hormone. Factors that decrease phosphate absorption: PTH, FGF23, High phosphate diet, Metabolic acidosis, Potassium deficiency, Glucocorticoids,Dopamine, Hypertension, Estrogen. Dietary factors regulating renal phosphate handling: In normal renal function, ingestion of phosphorus-containing foods leads to removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, thereby decreasing phosphate reabsorption from the ultrafiltrate. Dietary Pi restriction leads to insertion of the sodium phosphate cotransporters in the proximal tubule brush border membrane, increasing phosphate reabsorption.
In animals with normal renal function, ingestion of phosphorus-containing foods leads to removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, thereby decreasing phosphate reabsorption from the ultrafiltrate. By contrast, dietary Pi restriction leads to in- sertion of the sodium phosphate cotransporters in the prox- imal tubule brush border membrane, increasing phosphate reabsorption.
Potassium deficiency leads to an increase in phosphate excretion in the urine despite a paradoxical increase in the abundance of Npt2a in the proximal tubule brush border membrane that should increase phosphate reabsorption.
Hormonal and Other Factors Regulating Renal Phosphate Handling
PTH
PTH causes decreased renal reabsorption of phos- phate and phosphaturia by decreasing the abundance of Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane .
Fibroblast Growth Factor-23
To exert its physiologic effects on the proximal tubule, FGF23 requires the presence of a cofactor, Klotho, which is produced in the kidney and activates FGF receptor 1.
FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter.
FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1a- hydroxylase, which is the rate-limiting step in calcitriol synthesis, and increasing renal expression of 24-hydroxylase, which is required for calcitriol degradation .
In addition, FGF23 suppresses PTH synthesis, although the parathyroid glands are believed to become resistant to FGF23 as kidney disease progresses.
1,25(OH)2D.
Calcitriol is believed to increase phosphate reabsorption in the proximal tubule but the effects are confounded by the fact that changes in 1,25(OH)2D also alter plasma calcium and PTH levels.
Glucocorticoids.
Increased glucocorticoid levels lead to decreased proximal tubule synthesis and abundance of Npt2a as well as changes in brush border membrane lipid composition, which is thought to modulate sodium phosphate cotransporter activity . Estrogen.
Estrogen causes phosphaturia by decreasing the abundance of Npt2a in the proximal tubule without altering Npt2c levels .Estrogen also increases FGF23 synthesis . Thyroid Hormone.
Increased levels of thyroid hormone increase phosphate absorption by increasing proximal tubule transcription and expression of Npt2a .The Npt2a gene contains a thyroid response element and transcription of Npt2a mRNA is regulated by 3,5,3-tri- iodothyronine . Dopamine.
Dopamine leads to phosphaturia by inducing internalization of Npt2a from the proximal tubule brush border membrane. Dopamine-mediated internalization of Npt2a is dependent on a scaffolding protein (sodium-hydrogen exchanger regulatory factor 1) because dopamine does not induce phosphaturia in sodium-hydrogen exchanger regu- latory factor 1 knockout mice . Metabolic Acidosis.
Metabolic acidosis stimulates phosphaturia, which helps remove acid from the blood because phosphate serves as a titratable acid .By contrast, metabolic alkalosis increases renal phosphate absorption .
as the main control of phosphate reabsorption is the expression of NPT2 a,c in proximal convoluted tubules, diet and hormone play on this mechanism:
high phosphate diet, glucorticoids, estrogen, PTH, FGF23, and thyroid hormones decrease abundance of these transporters inducing phosphaturia
Dietary factors regulating renal phosphate handling:
In normal renal function, ingestion of phosphorus-containing foods leads to removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, thereby decreasing phosphate reabsorption from the ultrafiltrate.
By contrast, dietary Pi restriction leads to insertion of the sodium phosphate cotransporters in the proximal tubule brush border membrane, increasing phosphate reabsorption.
Hormonal and otherFactors Regulating Renal Phosphate Handling:
PTH: PTH causes decreased renal reabsorption of phosphate and phosphaturia by decreasing the abundance of Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane.
Fibroblast Growth Factor-23: (FGF23) is produced in osteoblasts in response to increases in serum Pi. FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter. FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1a- hydroxylase and increasing renal expression of 24-hydroxylase, which is required for calcitriol degradation.
1,25(OH)2D. Calcitriol is believed to increase phosphate reabsorption in the proximal tubule
Glucocorticoids. Increased glucocorticoid levels lead to decreased proximal tubule synthesis and abundance of Npt2a as well as changes in brush border membrane lipid composition, which is thought to modulate sodium phos- phate cotransporter activity
Estrogen. Estrogen causes phosphaturia by decreasing the abundance of Npt2a in the proximal tubule without altering Npt2c levels . Estrogen also increases FGF23 synthesis
Thyroid Hormone. Increased levels of thyroid hormone increase phosphate absorption by increasing proximal tubule transcription and expression of Npt2a .
Dopamine. Dopamine leads to phosphaturia by inducing internalization of Npt2a from the proximal tubule brush border membrane.
Metabolic Acidosis. Metabolic acidosis stimulates phos- phaturia, which helps remove acid from the blood because phosphate serves as a titratable acid . By contrast, met- abolic alkalosis increases renal phosphate absorption.
Hypertension. An acute increase in BP leads to decreased renal phosphate reabsorption by inducing removal of Npt2a from the proximal tubule brush border membrane microvilli to subapical endosomes.
+Dietary factors
In animals ingestion of phosphorous contain diet cause removal of Npt2a, Npt2c and Pit 2 from the brush border of proximal tubule so increase phosphorous excretion, potassium deficiency causes increase phosphorous excretion.
+Hormonal factor
*increase phosphate absorption include
Low phosphate diet, active vitamin D and increase thyroid hormones
*decrease phosphate absorption
PTH(decrease abundance of Npt2a, Npt2c and Pit 2 so increase phosphorous excretion) , FGF23(reduce the expression and activity of the cotransporter so increase excretion), high phosphate diet, metabolic acidosis( through the removal of phosphorous from the blood as phosphorous titratable acid) , potassium deficiency, glucocorticoids(decrease Npt2a expression and activity) , dopamine, hypertension(removal of Npt2a) , estrogen.
total amount of phosphate about 700 g. 85% is present in the bones and teeth, 14% in soft tissue.and the remaining 1% in the extracellular fluid.
normal Pi between( 2.5 and 4.5 mg/dL)
In plasma, phosphate exists as organic (70%) and inorganic (30%) forms
inorganic form is physiologically active. Only 10% of inorganic phosphate is bound to albumin.
three main organs are involved in phosphate homeostasis:
the intestine, the kidney, and the bone .
Of the filtered amount, about 80–90% is reabsorbed by the proximal tubule. Approximately 10% is reabsorbed by the distal convoluted tubule.
Little or no phosphate transport occurs in the Henle’s loop and collecting ducts.
Factors that inhibit phosphate reabsorption and increase excretion :
PTH :Inhibition of Na/Pi-IIa and IIc cotransports and Na/K-ATPase
FGF-23 Inhibition of type IIa and decreased formation of calcitriol by 1,α-hydroxylase inhibition.
Factors that promote phosphate reabsorption and decrease excretion
Parathyroidectomy Increased type IIa cotransporter activity.
Insulin Increased type IIa cotransporter activity .
Growth hormone Increased type IIa cotransporter activity Volume contraction Decreased GFR associated with increased Na+ reabsorption.
Metabolic alkalosis Increased type IIa cotransporter activity Increased type IIa . Hypermagnesemia Increased type IIa and type IIc cotransporter activity.
Dietary factors
High phosphate intake Inhibition of type IIa and IIc cotransporters in PCT thatinhibitphosphate reabsorption and increase excretion.
Low phosphate intake Increased type IIa and type IIc cotransporter activity increase phosphate reabsorption.
The level of phosphate in our body is regulated by humoral (hormonal and other factors) and dietary factors(daily intake between 700 and 2000mg). Around 85% of the phosphate reabsorption occurs within the proximal tubule of the kidneys. The amount of phosphate reabsorbed is determined by the abundance of cotransporters in the apical membrane of the proximal tubule cells.
Dietary factors, such as phosphorus-containing foods, can affect the reabsorption of phosphate. These foods remove cotransporters from the proximal tubule brush border membrane, decreasing phosphate reabsorption. Conversely, restricting dietary phosphate increases the abundance of cotransporters in the proximal tubule, increasing phosphate absorption.
Hormonal factors, such as PTH, FGF-23, and thyroid hormone, can also affect the reabsorption of phosphate. PTH decreases renal reabsorption of phosphate, while FGF-23 decreases the expression and activity of sodium phosphate cotransporters in the proximal tubule. Thyroid hormone increases phosphate absorption by increasing the expression of Npt2a.
Other factors, such as Calcitriol, glucocorticoids, estrogen, dopamine, metabolic acidosis, and hypertension, can also affect phosphate reabsorption , working on the same receptors.
Daily Phosphorus
In a steady state, urine and feces phosphate (Pi) excretion balance oral phosphorus intake. Phosphorus-rich foods like dairy may increase daily phosphorus intake by 700–2000 mg. Phosphate (31 mg/l elemental phosphorus and 51 mmol/l phosphate) crosses cell membranes after absorption.
Renal Phosphate Regulation by Diet:
In mice with normal renal function, phosphorus-containing diets remove Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, lowering ultrafiltrate phosphate reabsorption. Dietary Pi restriction induces sodium phosphate cotransporters in the proximal tubule brush border membrane, enhancing phosphate reabsorption.
hormones regulate renal phosphate handling.
PTH decreases Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane, lowering phosphate reabsorption and phosphaturia.
FGF-23. Osteoblasts create FGF23 as serum Pi rises. FGF23 needs the kidney-produced cofactor Klotho to activate FGF receptor 1 in the proximal tubule.
1,25(OH)2D. Calcitriol increases proximal tubule phosphate reabsorption, although variations in 1,25(OH)2D also affect plasma calcium and PTH.
Thyroxine. Thyroid hormone increases proximal tubule transcription and Npt2a expression to improve phosphate absorption.
Dopamine. Npt2a internalization from the proximal tubule brush boundary membrane by dopamine causes phosphaturia.
Acidosis. Metabolic acidosis causes phosphaturia, which removes blood acid since phosphate is a titratable acid.
Hypertension. Acute BP increases remove Npt2a from the proximal tubule brush border membrane microvilli to subapical endosomes, decreasing renal phosphate reabsorption.
Summarize the effect of humoral and dietary factors on phosphorus levels.
about 85% of phosphate reabsorption occurs within the proximal tubule
renal handling the pi reabsorption through three renal sodium phosphate cotransporters, Npt2a, Npt2c, and PiT-2,
present in the apical brush border membrane of renal proximal tubule cells
The amount of phosphate reabsorbed from the filtrate is determined by the abundance of the cotransporters in the apical membrane of proximal tubule cells
and affected by changes in brush border membrane lipid composition
so any factors affecting on the three cotransporter or the brush border membrane lipid composition will change in reabsorption of pi
phosphorus-containingfoods leads to >>>>> removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane,
so decreasing phosphate reabsorption from the ultrafiltrate.
And vice versa
dietary Pi restriction leads to abundance of cotransporter in proximal tubule and increase phosphate absorption Potassiumdeficiency leads to an increase in phosphate excretion in the urine
despite a paradoxical increase in the abundance of Npt2a in the proximal tubule brush border membrane that should increase phosphate reabsorption. Potassium deficiency leads to changes in the brush border membrane lipid composition lead to inhibit cotransporter activity 2-Hormonal and Other Factors Regulating Renal Phosphate Handling PTH causes decreased renal reabsorption of phosphate and phosphaturia by decreasing the abundance of Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane Fibroblast Growth Factor-23. FGF-23 is produced in osteoblasts in response to increases in serum Pi.
FGF23 requires the presence of a cofactor, Klotho, which is produced in the kidney and activates FGF receptor 1
FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule
and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter.
FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1hydroxylase
FGF23 suppresses PTH synthesis, although the parathyroid glands are believed to become resistant to FGF23 as kidney disease progresses. 1,25(OH)2D. Calcitriol
is believed to increase phosphate reabsorption in the proximal tubule
but the effects are confounded by the fact that changes in 1,25(OH)2D also alter plasma calcium and PTH levels. Glucocorticoids
Increased glucocorticoid levels lead to decreased proximal tubule synthesis and abundance of Npt2a as well as changes in brush border membrane lipid composition, which is thought to modulate sodium phosphate cotransporter activity so decrease phosphate absorption
Estrogen. Estrogen causes phosphaturia by decreasing the abundance of Npt2a in the proximal tubule without altering Npt2c levels
Estrogen also increases FGF23 synthesis Thyroid hormone
Increased levels of thyroid hormone increase phosphate absorption by increasing proximal tubule transcription and expression of Npt2a Dopamine
Has Phosphaturia effect by inducing internalization of Npt2a from the proximal tubule brush border membrane Metabolic Acidosis.
Metabolic acidosis stimulates phosphaturia Hypertension.
Increasing blood pressure lead to decrease phosphate reabsorption
Maintenance of serum phosphate within the normal range depends on a complex interplay between absorption of phosphate in the gut, exchange with bone stores, shifts between intracellular and ECF
Dietary or hormonal changes result in insertion or removal of NaPit2 from the brush border membrane of PCT, which may be rapid (min-hrs) in NaPit2a or slow (hrs-days) in NaPit2c.
Factors Increase phosphate absorption
Low-PO4 diet, Hyperthyroidism, Active vit D
Factors Decrease phosphate absorption
PTH, FGF-23, Acidosis, HTN, high dietary PO4, Glucocorticoids
ingestion of phosphorus-containing foods leads to removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, thereby decreasing phosphate reabsorption from the ultrafiltrate and the opp
Potassium deficiency leads to an increase in phosphate excretion .Potassium deficiency leads to changes in the brush border
membrane lipid composition that are thought to inhibit Npt2a activity
PTH causes decreased renal reabsorption of phosphate and phosphaturia by decreasing the abundance of Npt2a ( within minute ) Npt2c, and PiT-2 ( within hours ) in the renal proximal tubule brush border membrane
A low-fosfat diet increases the absorption of available phosphor from the intestines. On the other hand diet rich in phosphorous decreases absorption.
Thyroid hormone and active vitamin D increase the Pi absorption. This favours hyperphosphatemia.
PTH decreases Pi absorption and exerts phpaturic effect on the kidney. This is usually by reducing the abundance of Npt2a, Npt2c and PiT in the proximal renal tubule.
FGF-23: phosphaturic hormone, increases when Pi is increasing, synthesized by osteoblast and requires Klotho (synthesized in the kidney) for action
–FGF-23 reduces the expression and activity of Na-P cotransporters in PCT
–Thought to decrease the activity of intestinal Na-Pi cotransporters.
— decrease levels of calcitriol by decreasing expression of 1 alpha-hydroxylase
1,25 (OH)2 vştamin D: thought to increase reabsorption by PCT.
Dietary and humoral factors on phosphorus level:
The kidneys are the major regulators of Pi homeostasis, Dietary or hormonal changes result in insertion or removal of NaPit2 from the brush border membrane of PCT, which may be rapid (min-hrs) in NaPit2a or slow (hrs-days) in NaPit2c.
Dietary phosphorus: High phosphate diet -> down regulation of PCT NaPit2a,c -> decreased phosphate reabsorption. Pi restriction causes increased phosphate reabsorption
Hypokalemia leads to confirmational changes in brush border of PCT-> reduced NaPit2a,c activity inspite abundance-> reduced Pi reabsorption.
PTH: phosphaturic hormone-> down regulation of PCT NaPit2a (within minutes) & NaPit2c (within hrs)-> decreased phosphate reabsorption.
FGF23 (phosphaturic)-> down regulation of
NaPit2b -> decreased Intestinal phosphate absorption. Also inhibits 1alphahydroxylase decreases vitamin D activation decreasing Pi absorption and reabsorption.
1,25 OH D: increases intestinal Pi absorption and PCT reabsorption.
Glucocorticoids: increased Glucocorticoid level leads to confirmational changes in brush border of PCT, also it down regulates PCT NaPit2a -> decreased PCT phosphate reabsorption
Dietary Factors Regulating Renal Phosphate Handling:
ingestion of phosphorus-containing foods leads to decreasing phosphate reabsorption from the ultrafiltrate. By contrast, dietary Pi restriction leads to increasing phosphate reabsorption.
Potassium deficiency leads to an increase in phosphate excretion in the urine. Potassium deficiency leads to changes in the brush border membrane lipid composition that are thought to inhibit Npt2a activity.
Hormonal and Other Factors Regulating Renal Phosphate:
PTH causes decreased renal reabsorption of phosphate and phosphaturia.
Fibroblast growth factor23 (FGF23) is produced in osteoblasts in response to increases in serum Pi. To exert its physiologic effects on the proximal tubule, FGF23 requires the presence of a cofactor, Klotho, which is produced in the kidney and activates FGF receptor 1. FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter. FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1ahydroxylase, which is the rate-limiting step in calcitriol synthesis, and increasing renal expression of 24-hydroxylase, which is required for calcitriol degradation. In addition, FGF23 suppresses PTH synthesis, although the parathyroid glands are believed to become resistant to FGF23 as kidney disease progresses.
1,25(OH)2D. Calcitriol is believed to increase phosph reabsorption in the proximal tubule but the effects are confounded by the fact that changes in 1,25(OH)2Dalso alter plasma calcium and PTH levels.
Glucocorticoids. Increased glucocorticoid levels lead to decreased proximal tubule synthesis and abundance of Npt2a as well as changes in brush border membrane lipid composition, which is thought to modulate sodium phosphate cotransporter activity. Estrogen causes phosphaturia by decreasing
the abundance of Npt2a in the proximal tubule without altering Npt2c levels.
Thyroid Hormone increase phosphate absorption by increasing proximal tubule transcription and expression of Npt2a.
Dopamine leads to phosphaturia by inducing internalization of Npt2a from the proximal tubule brush border membrane. Dopamine-mediated internalization of Npt2a is dependent on a scaffolding protein (sodium-hydrogen exchanger regulatory factor 1) Metabolic acidosis stimulates phosphaturia, which helps remove acid from the blood because phosphate serves as a titratable acid metabolic alkalosis increases renal phosphate absorption .
Summarize the effect of humoral and dietary factors on phosphorus levels.Dietary factors regulating renal phosphate handling:
Hormonal and Other Factors Regulating Renal Phosphate Handling:
Increase phosphate absorption
Low-PO4 diet, Hyperthyroidism, Active vit D
Decrease phosphate absorption
PTH, FGF-23, Acidosis, HTN, high dietary PO4, Glucocorticoids
Factors that increase phosphate absorption: Low phosphate diet, 1,25-vitD3, Thyroid hormone.
Factors that decrease phosphate absorption: PTH, FGF23, High phosphate diet, Metabolic acidosis, Potassium deficiency, Glucocorticoids,Dopamine, Hypertension, Estrogen.
Dietary factors regulating renal phosphate handling:
In normal renal function, ingestion of phosphorus-containing foods leads to removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, thereby decreasing phosphate reabsorption from the ultrafiltrate.
Dietary Pi restriction leads to insertion of the sodium phosphate cotransporters in the proximal tubule brush border membrane, increasing phosphate reabsorption.
Dietary Factors Regulating Renal Phosphate Handling :
In animals with normal renal function, ingestion of phosphorus-containing foods leads to removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, thereby decreasing phosphate reabsorption from the ultrafiltrate. By contrast, dietary Pi restriction leads to in- sertion of the sodium phosphate cotransporters in the prox- imal tubule brush border membrane, increasing phosphate reabsorption.
Potassium deficiency leads to an increase in phosphate excretion in the urine despite a paradoxical increase in the abundance of Npt2a in the proximal tubule brush border membrane that should increase phosphate reabsorption.
Hormonal and Other Factors Regulating Renal Phosphate Handling
PTH
PTH causes decreased renal reabsorption of phos- phate and phosphaturia by decreasing the abundance of Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane .
Fibroblast Growth Factor-23
To exert its physiologic effects on the proximal tubule, FGF23 requires the presence of a cofactor, Klotho, which is produced in the kidney and activates FGF receptor 1.
FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter.
FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1a- hydroxylase, which is the rate-limiting step in calcitriol synthesis, and increasing renal expression of 24-hydroxylase, which is required for calcitriol degradation .
In addition, FGF23 suppresses PTH synthesis, although the parathyroid glands are believed to become resistant to FGF23 as kidney disease progresses.
1,25(OH)2D.
Calcitriol is believed to increase phosphate reabsorption in the proximal tubule but the effects are confounded by the fact that changes in 1,25(OH)2D also alter plasma calcium and PTH levels.
Glucocorticoids.
Increased glucocorticoid levels lead to decreased proximal tubule synthesis and abundance of Npt2a as well as changes in brush border membrane lipid composition, which is thought to modulate sodium phosphate cotransporter activity .
Estrogen.
Estrogen causes phosphaturia by decreasing the abundance of Npt2a in the proximal tubule without altering Npt2c levels .Estrogen also increases FGF23 synthesis .
Thyroid Hormone.
Increased levels of thyroid hormone increase phosphate absorption by increasing proximal tubule transcription and expression of Npt2a .The Npt2a gene contains a thyroid response element and transcription of Npt2a mRNA is regulated by 3,5,3-tri- iodothyronine .
Dopamine.
Dopamine leads to phosphaturia by inducing internalization of Npt2a from the proximal tubule brush border membrane. Dopamine-mediated internalization of Npt2a is dependent on a scaffolding protein (sodium-hydrogen exchanger regulatory factor 1) because dopamine does not induce phosphaturia in sodium-hydrogen exchanger regu- latory factor 1 knockout mice .
Metabolic Acidosis.
Metabolic acidosis stimulates phosphaturia, which helps remove acid from the blood because phosphate serves as a titratable acid .By contrast, metabolic alkalosis increases renal phosphate absorption .
as the main control of phosphate reabsorption is the expression of NPT2 a,c in proximal convoluted tubules, diet and hormone play on this mechanism:
high phosphate diet, glucorticoids, estrogen, PTH, FGF23, and thyroid hormones decrease abundance of these transporters inducing phosphaturia
Dietary factors regulating renal phosphate handling:
In normal renal function, ingestion of phosphorus-containing foods leads to removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, thereby decreasing phosphate reabsorption from the ultrafiltrate.
By contrast, dietary Pi restriction leads to insertion of the sodium phosphate cotransporters in the proximal tubule brush border membrane, increasing phosphate reabsorption.
Hormonal and otherFactors Regulating Renal Phosphate Handling:
PTH: PTH causes decreased renal reabsorption of phosphate and phosphaturia by decreasing the abundance of Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane.
Fibroblast Growth Factor-23: (FGF23) is produced in osteoblasts in response to increases in serum Pi. FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter. FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1a- hydroxylase and increasing renal expression of 24-hydroxylase, which is required for calcitriol degradation.
1,25(OH)2D. Calcitriol is believed to increase phosphate reabsorption in the proximal tubule
Glucocorticoids. Increased glucocorticoid levels lead to decreased proximal tubule synthesis and abundance of Npt2a as well as changes in brush border membrane lipid composition, which is thought to modulate sodium phos- phate cotransporter activity
Estrogen. Estrogen causes phosphaturia by decreasing the abundance of Npt2a in the proximal tubule without altering Npt2c levels . Estrogen also increases FGF23 synthesis
Thyroid Hormone. Increased levels of thyroid hormone increase phosphate absorption by increasing proximal tubule transcription and expression of Npt2a .
Dopamine. Dopamine leads to phosphaturia by inducing internalization of Npt2a from the proximal tubule brush border membrane.
Metabolic Acidosis. Metabolic acidosis stimulates phos- phaturia, which helps remove acid from the blood because phosphate serves as a titratable acid . By contrast, met- abolic alkalosis increases renal phosphate absorption.
Hypertension. An acute increase in BP leads to decreased renal phosphate reabsorption by inducing removal of Npt2a from the proximal tubule brush border membrane microvilli to subapical endosomes.
Summarize the effect of humoral and dietary factors on phosphorus levels.
Factors Increase phosphate absorption
Low-phosphate diet,1,25 Vit D3,Thyroid hormone
Decrease phosphate absorption
Pth ,FGF23,High phosphate diet,Metabolic acidosis
Hypokalemia,Steroids,Dopamine
Estrogen,Hypertyension
+Dietary factors
In animals ingestion of phosphorous contain diet cause removal of Npt2a, Npt2c and Pit 2 from the brush border of proximal tubule so increase phosphorous excretion, potassium deficiency causes increase phosphorous excretion.
+Hormonal factor
*increase phosphate absorption include
Low phosphate diet, active vitamin D and increase thyroid hormones
*decrease phosphate absorption
PTH(decrease abundance of Npt2a, Npt2c and Pit 2 so increase phosphorous excretion) , FGF23(reduce the expression and activity of the cotransporter so increase excretion), high phosphate diet, metabolic acidosis( through the removal of phosphorous from the blood as phosphorous titratable acid) , potassium deficiency, glucocorticoids(decrease Npt2a expression and activity) , dopamine, hypertension(removal of Npt2a) , estrogen.
total amount of phosphate about 700 g. 85% is present in the bones and teeth, 14% in soft tissue.and the remaining 1% in the extracellular fluid.
normal Pi between( 2.5 and 4.5 mg/dL)
In plasma, phosphate exists as organic (70%) and inorganic (30%) forms
inorganic form is physiologically active. Only 10% of inorganic phosphate is bound to albumin.
three main organs are involved in phosphate homeostasis:
the intestine, the kidney, and the bone .
Of the filtered amount, about 80–90% is reabsorbed by the proximal tubule. Approximately 10% is reabsorbed by the distal convoluted tubule.
Little or no phosphate transport occurs in the Henle’s loop and collecting ducts.
Factors that inhibit phosphate reabsorption and increase excretion :
Factors that promote phosphate reabsorption and decrease excretion
Dietary factors
The level of phosphate in our body is regulated by humoral (hormonal and other factors) and dietary factors(daily intake between 700 and 2000mg). Around 85% of the phosphate reabsorption occurs within the proximal tubule of the kidneys. The amount of phosphate reabsorbed is determined by the abundance of cotransporters in the apical membrane of the proximal tubule cells.
Dietary factors, such as phosphorus-containing foods, can affect the reabsorption of phosphate. These foods remove cotransporters from the proximal tubule brush border membrane, decreasing phosphate reabsorption. Conversely, restricting dietary phosphate increases the abundance of cotransporters in the proximal tubule, increasing phosphate absorption.
Hormonal factors, such as PTH, FGF-23, and thyroid hormone, can also affect the reabsorption of phosphate. PTH decreases renal reabsorption of phosphate, while FGF-23 decreases the expression and activity of sodium phosphate cotransporters in the proximal tubule. Thyroid hormone increases phosphate absorption by increasing the expression of Npt2a.
Other factors, such as Calcitriol, glucocorticoids, estrogen, dopamine, metabolic acidosis, and hypertension, can also affect phosphate reabsorption , working on the same receptors.
The phosphorus balance
Daily balance
GIT phosphate absorption
Renal regulation of phosphate
Alteration of phosphate balance can lead to;
Daily Phosphorus
In a steady state, urine and feces phosphate (Pi) excretion balance oral phosphorus intake. Phosphorus-rich foods like dairy may increase daily phosphorus intake by 700–2000 mg. Phosphate (31 mg/l elemental phosphorus and 51 mmol/l phosphate) crosses cell membranes after absorption.
Renal Phosphate Regulation by Diet:
In mice with normal renal function, phosphorus-containing diets remove Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane, lowering ultrafiltrate phosphate reabsorption. Dietary Pi restriction induces sodium phosphate cotransporters in the proximal tubule brush border membrane, enhancing phosphate reabsorption.
hormones regulate renal phosphate handling.
PTH decreases Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane, lowering phosphate reabsorption and phosphaturia.
FGF-23. Osteoblasts create FGF23 as serum Pi rises. FGF23 needs the kidney-produced cofactor Klotho to activate FGF receptor 1 in the proximal tubule.
1,25(OH)2D. Calcitriol increases proximal tubule phosphate reabsorption, although variations in 1,25(OH)2D also affect plasma calcium and PTH.
Glucocorticoids. Glucocorticoids reduce proximal tubule production, Npt2a abundance, and brush boundary membrane lipid composition.
Estrogen. Estrogen decreases proximal tubule Npt2a without affecting Npt2c, causing phosphaturia. Estrogen boosts FGF23 production.
Thyroxine. Thyroid hormone increases proximal tubule transcription and Npt2a expression to improve phosphate absorption.
Dopamine. Npt2a internalization from the proximal tubule brush boundary membrane by dopamine causes phosphaturia.
Acidosis. Metabolic acidosis causes phosphaturia, which removes blood acid since phosphate is a titratable acid.
Hypertension. Acute BP increases remove Npt2a from the proximal tubule brush border membrane microvilli to subapical endosomes, decreasing renal phosphate reabsorption.
Summarize the effect of humoral and dietary factors on phosphorus levels.
about 85% of phosphate reabsorption occurs within the proximal tubule
renal handling the pi reabsorption through three renal sodium phosphate cotransporters, Npt2a, Npt2c, and PiT-2,
present in the apical brush border membrane of renal proximal tubule cells
The amount of phosphate reabsorbed from the filtrate is determined by the abundance of the cotransporters in the apical membrane of proximal tubule cells
and affected by changes in brush border membrane lipid composition
so any factors affecting on the three cotransporter or the brush border membrane lipid composition will change in reabsorption of pi
1-Dietary Factors Regulating Renal Phosphate Handling
phosphorus-containing foods leads to >>>>> removal of Npt2a, Npt2c, and PiT-2 from the proximal tubule brush border membrane,
so decreasing phosphate reabsorption from the ultrafiltrate.
And vice versa
dietary Pi restriction leads to abundance of cotransporter in proximal tubule and increase phosphate absorption
Potassium deficiency leads to an increase in phosphate excretion in the urine
despite a paradoxical increase in the abundance of Npt2a in the proximal tubule brush border membrane that should increase phosphate reabsorption.
Potassium deficiency leads to changes in the brush border membrane lipid composition lead to inhibit cotransporter activity
2-Hormonal and Other Factors Regulating Renal Phosphate Handling
PTH causes decreased renal reabsorption of phosphate and phosphaturia by decreasing the abundance of Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane
Fibroblast Growth Factor-23. FGF-23 is produced in osteoblasts in response to increases in serum Pi.
FGF23 requires the presence of a cofactor, Klotho, which is produced in the kidney and activates FGF receptor 1
FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule
and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter.
FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1hydroxylase
FGF23 suppresses PTH synthesis, although the parathyroid glands are believed to become resistant to FGF23 as kidney disease progresses.
1,25(OH)2D. Calcitriol
is believed to increase phosphate reabsorption in the proximal tubule
but the effects are confounded by the fact that changes in 1,25(OH)2D also alter plasma calcium and PTH levels.
Glucocorticoids
Increased glucocorticoid levels lead to decreased proximal tubule synthesis and abundance of Npt2a as well as changes in brush border membrane lipid composition, which is thought to modulate sodium phosphate cotransporter activity so decrease phosphate absorption
Estrogen.
Estrogen causes phosphaturia by decreasing the abundance of Npt2a in the proximal tubule without altering Npt2c levels
Estrogen also increases FGF23 synthesis
Thyroid hormone
Increased levels of thyroid hormone increase phosphate absorption by increasing proximal tubule transcription and expression of Npt2a
Dopamine
Has Phosphaturia effect by inducing internalization of Npt2a from the proximal tubule brush border membrane
Metabolic Acidosis.
Metabolic acidosis stimulates phosphaturia
Hypertension.
Increasing blood pressure lead to decrease phosphate reabsorption
Summarize the effect of humoral and dietary factors on phosphorus levels.
Factors that alter renal regulation of phosphate
A.Increase phosphate absorption
B.Decrease phosphate absorption