Transcript Regulation of Phosphate Transport in Proximal Tubule

TmP/GFR = maximum reabsorption of
PO4 per unit volume of GFR
FEPO4 = UPO4 /PPO4 / Ucreat /Pcreat
1 - FEPO4 = TRP
Assuming PPO4 = [PO4]GFR
TmPO4/GFR = TRP X PPO4
• Tubular reabsoption of phosphate (TRP)
• Tubular maximal reabsoption rate of
phosphate to GFR (TmP/GFR)
• TRP =99.9%
• TmP/GFR = TRP x Plasma Phos = 0.999
x 0.93 mmol/L (converted from 2.9 mg/dL)
= 0.93 mmol/L
Regulation of Phosphate
Transport in Proximal Tubule
Alexander Usorov, MD
11/25/08
Overview
• Role of phosphorus
• Proximal nephron transport mechanism
• Sodium-hydrogen exchanger
regulatory factor-1 (NHERF1)
• Fibroblast Growth Factor (FGF 23)
Importance of Phosphorus
• Component of hydroxyapatite, which is the major
component of bone mineral
• Present in nucleic acids, bioactive signaling
proteins, phosophorylated enzymes, and cell
membranes
• Deficiency in phosphorus leads to
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Impaired bone mineralization (osteomalacia or rickets)
Abnormal RBC, WBC, Plt fxn
Impaired cell membrane integrity (rhabdo)
Impaired cardiac output
Phosphorus Metabolism
1500mg
1100mg
200mg
200mg
Phosphorus reabsorption
• Up to 95% occurs in the proximal tubule
• Filtered phosphate moves from lumen to
cells via Na-phosphate cotransporters
located in the luminal membrane
• Different types of Na/Pi cotransporters
– NaPi-2a (encoded by SLC34A1 gene, mediates
70% of filtered phosphate)
– NaPi-2c (encoded by SLC34A3 gene)
– Pit-1/2
Different stoichiometries
• NaPi-2a is electrogenic
– Stoichiometry is 3:1 Na:P
• NaPi-2c is eletroneutral
– Stoichiometry is 2:1
• Both cotransporters show similar affinity fo Na
(-50mM) and Pi (<0.1mM)
• Why is stoichiometry important?
– It allows the favorable inward gradient to drive continued
phosphate uptake despite a falling tubular fluid phosphate
concentration
The role of NHERF-1
• Sodium-hydrogen exchanger
regulatory factor 1 protein
• Interacts with C-terminal tail of NaPi-2a
and NaPi-2c
• Plays an important role in the
trafficking and transciptional regulation
NHERF-1 Cont
• Recent study by Karim et al in NEJM from
September 2008
• Gene sequencing of patients with renal stones, bone
demineralization, or both (usual causes such as
hyperparathyroidism were excluded)
• Three different NHERF1 mutations in 7 patients,
which had a significantly lower renal phosphate
reabsorption capacities than patients with wild type
NHERF1
– Greater cAMP stimulation and greater inhibition of
phosphate transport in the presence of PTH
Phosphatonins
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Term was coined in 1994 to describe a circulating phosphaturic factor present
in patient with oncogenic or Tumor-induced osteomalacia
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Hypophosphatemia
Renal phosphate wasting
Reduced 1,25 Vit D
Osteomalacia
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All resolved after removal of the tumor
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Include:
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Fibroblast growth factor 23 (FGF-23)
FGF-7
matrix extracellular phosphoglycoprotein (MEPE)
secreted frizzled-related protein 4 (sFRP-4)
Phosphatonins downregulate renal phosphate reabsorption at least in part by
decreasing the abundance of apical sodium/phosphate co-transporters in the
proximal tubule (both NaPi-2a and NaPi-2c)
FGF-23
• Elevated in the following disorders (phenotypically
similar to TIO):
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X-linked hypophosphatemic rickets (XLH)
Autosomal dominant hypophosphatemic rickets (ADHR)
Autosomal recessive hypophosphatemia (ARHP)
Renal failure (correlates with decline in GFR as well as
elevated phos) <- phenotypically different from TIO
• Reduced in Tumoral calcinosis, a disorder
characterized by:
– Hyperphosphatemia
– Reduced fractional excretion of phosphate
– Ca phosphate deposits in soft tissues
FGF-23
• Secreted, circulating 32kDa protein
• Predominantly expressed in osteocytes in the bone and
endothelial cells of bone marrow and thymus
• Interacts with FGF receptors that belong to type 1
transmembrane phosphotyrosine kinase receptors
(MAPK/ERK1-2)
• Requires Klotho as a co-factor for receptor activation
– Klotho gene encodes a single-pass membrane protein,
homologous to B-glucosidase
– Klotho-deficient mice have a phenotype similar to FGF-23 null mice
FGF 23