Transcript Renal tubular reabsorption

Renal tubular reabsorption
Stephen P. DiBartola
Department of Veterinary Clinical Sciences
College of Veterinary Medicine
Ohio State University
Columbus OH 43210
What do the kidneys do?
The glomeruli “non-discriminantly” filter the blood, and the
tubules take back what the body needs leaving the rest as waste
to be excreted. Some wastes also can be actively added to the
tubular fluid.
Renal tubular reabsorption
• Excretion refers to the removal of solutes
and water from the body in urine
• Reabsorption (movement from tubular
fluid to peritubular blood) and secretion
(movement from peritubular blood to
tubular fluid) refer to direction of
movement of solutes and water across the
renal tubular epithelium
Renal tubular reabsorption
• The luminal cell membranes are
those that face the tubular lumen
(“urine” side)
• The basolateral cell membranes are
those are in contact with the lateral
intercellular spaces and peritubular
interstitium (“blood” side)
Renal tubular reabsorption
• The transmembrane potential
difference is the electrical potential
difference between the inside and
outside of the cell
• The transepithelial potential
difference is the electrical potential
difference between the tubular lumen
and the peritubular interstitium
Renal tubular reabsorption
• The term transcellular refers to
movement of solutes and water through
cells
• The term paracellular refers to
movement of solutes and water between
cells
• Epithelial cell junctions can be “leaky”
(proximal tubule) or “tight” (distal
convoluted tubule, collecting duct)
Terminology
Transepithelial versus
transmembrane potential
difference
Luminal versus basolateral
membranes
Transcellular versus paracellular
transport
Renal tubular reabsorption
• Leaky epithelia
(proximal)
• Tight epithelial
(distal)
• Small
transepithelial
concentration
difference
• Small TEPD
• High water
permeability
• Large
transepithelial
concentration
difference
• Large TEPD
• Low water
permeability
Nephro-man says …
Just think
of it as a
six-pack
Luminal surface
Epithelial tight
junctions
Basolateral surface
Renal tubular reabsorption
That renal tubular reabsorption must
occur is intuitively obvious because …
The fluid filtered into Bowman’s space is
an ultrafiltrate of plasma containing
many vital small molecular weight
solutes (e.g., glucose, amino acids,
bicarbonate) but these solutes do not
normally appear in urine
Renal tubular reabsorption
• Solute reaborption in the proximal tubule
is isosmotic (water follows solute
osmotically and tubular fluid osmolality
remains similar to that of plasma)
• 65% of water and solute reabsorption
occurs in the proximal tubule
• 90% of bicarbonate
• 99% of glucose & amino acids
• Proximal tubules: coarse adjustment
• Distal tubules: fine adjustment
Cl- goes up
because Na+ is
reabsorbed with
glucose, amino
acids, Pi and
HCO3Unchanged
due to
isosmotic
reabsorption
Glucose, amino
acids, Pi and
HCO3- go down
due to
reabsorption with
Na+
Secondary active co-transport
(glucose, amino acids, phosphate)
LUMINAL
Glucose, Pi
amino acids
Na+
HCO3-
Na+
+ H+
H2CO3
BASOLATERAL
2 K+
3 Na+
K+
Types of transport processes
•
•
•
•
•
•
Passive transport (simple diffusion)
Facilitated diffusion
Primary active transport
Secondary active transport
Pinocytosis
Solvent drag
Passive transport (simple diffusion):
Definition
• Movement of a
substance across
a membrane as a
result of random
molecular motion
Passive transport (simple
diffusion): Characteristics
• No metabolic energy
required
• Rate of transfer dependent
on electrochemical gradient
across membrane and
membrane permeability
characteristics
• Rate of transfer linearly
related to concentration of
diffusion substance (no Vmax)
Facilitated diffusion: Definition
• Movement of a substance across
a membrane down its
electrochemical gradient after
binding with a specific carrier
protein in the membrane
Facilitated diffusion: Characteristics
• Saturable (has a Vmax)
• Structural specificity and affinity of
carrier for substance transported
• Transfer may occur in either direction
across membrane
• Does not directly require metabolic
energy
Facilitated diffusion: Examples
• Glucose, amino acids:
Basolateral membranes of
proximal tubules
• Sodium: luminal membranes of
proximal tubules
Primary active transport:
Definition
• Movement of a substance across
a membrane in combination with
a carrier protein but against an
electrochemical gradient
Primary active transport:
Characteristics
• Directly requires metabolic
energy (i.e. hydrolysis of ATP)
• Saturable (has a Vmax)
• Structural specificity and affinity
of the carrier for the substance
transported
Primary active transport:
Examples
•
•
•
•
Na+-K+ ATPase
H+ ATPase
H+-K+ ATPase
Ca+2 ATPase
Secondary active transport:
Definition
• Two substances interact with one
specific carrier in the cell membrane
and both substances are translocated
across the membrane
• Co-transport Transported substances
move in the same direction across the
membrane
• Counter-transport Transported
substances move in opposite directions
across the membrane
Secondary active transport:
Characteristics
• “Uphill” transport of one substance is linked to
“downhill” transport of another substance
• Carrier must be occupied by both substances
(or be unoccupied) to be mobile in the
membrane
• Saturable (has a Vmax)
• Demonstrates specificity and affinity of carrier
for substance transported
• “Uphill” transport occurs without direct input of
metabolic energy
Secondary active transport:
Examples
• Glucose, amino acids, or
phosphate with sodium in luminal
membranes of proximal tubules
• Sodium and hydrogen ions in
luminal membranes of proximal
tubules
Secondary active transport
• The metabolic energy for secondary
active transport of Na+ at the luminal
membrane in the proximal tubule
comes from Na+-K+ ATPase which
transports Na+ out of the cell across
the basolateral membrane and
maintains a favorable electrochemical
gradient for the entry of Na+ at the
luminal membrane
Secondary active co-transport
(glucose, amino acids, phosphate)
LUMINAL
Glucose, Pi
amino acids
Na+
HCO3-
Na+
+ H+
H2CO3
BASOLATERAL
2 K+
3 Na+
K+
Pinocytosis
• Definition: Uptake by cells of
particles too large to diffuse
through the cell membrane
• Example: Reabsorption of filtered
proteins in the proximal tubules
Solvent drag: Definition
• A solvent such as water moving
across an epithelium by osmosis
can drag dissolved solutes with it
Morphologic features of
proximal tubular cells
• Large surface area for
reabsorption of water
and solutes (brush
border, lateral cellular
interdigitations)
• Large numbers of
mitochondria to provide
ATP
• Leaky epithelial
junctions
Routes of transport across
proximal tubular epithelium
• Paracellular
• 1% of surface area
• 5-10% of water transfer
• Passive diffusion or
solvent drag only
• Requires favorable
electrochemical
gradient
• Passive diffusion of
ions and large nonpolar solutes
• Transcellular
• 99% of surface area
• 90-95% of water transfer
• Passive or active
transport
• All active transport
occurs by this route
Intrasegmental axial heterogeneity
of proximal tubule
• P1: sodium, water,
bicarbonate, amino
acids, glucose, and
phosphate reabsorbed
• P2: sodium, water and
chloride reabsorbed
• P3: Organic acids and
bases transported
Secondary active transport
• Glucose, Amino acids
• Tmax high and constant (kidney not a
regulator of plasma glucose and amino
acid concentrations)
• Phosphate
• Tmax low and altered by PTH (kidney is a
regulator of plasma phosphtate
concentration)
Secondary active transport:
Glucose
Secondary active transport:
Phosphate
Na+-K+ ATPase
• In renal tubular cells found only in
basolateral membrane
• When ATP is hydrolyzed, 2 K+ ions are
pumped into the cell and 3 Na+ ions are
pumped out
• Maintains favorable electrochemical
gradient for Na+ entry at luminal
membrane
• Maintains cell membrane potential
difference and intracellular osmolality
Pinocytosis
• Endocytosis: Filtered proteins
adsorbed to sites on luminal
membranes that are internalized to
form endosomes. Fusion with
lysosomes forms endolysosomes in
which digestion of proteins occurs
• Hydrolysis of filtered proteins to
constituent amino acids by enzymes in
brush border of proximal tubular cells
Urea: Passive diffusion
• Urea is passively reabsorbed in the
proximal tubule
• More urea is reabsorbed at low tubular
flow rates than at high tubular flow
rates
• Contributes to BUN increasing out of
proportion to creatinine in dehydrated
patients even before GFR decreases
Calcium homeostasis
• 99% of Ca+2 in bone, < 1%
intracellular, 0.1% extracellular
• Much homeostasis achieved by
altering GI absorption via calcitriol
• Only 60% of plasma Ca+2 (ionized and
complexed) is available for
glomerular filtration
Renal handling of Ca+2
• Filtered by glomeruli and reabsorbed
by tubules
• 99% of filtered Ca+2 is reabsorbed
(exception: horse)
• Proximal tubule: 60-65%
• Loop of Henle: 25-30%
• Distal tubule & collecting duct: 4-9%
Renal reabsorption of Ca+2
• Proximal tubule, medullary thick
ascending loop of Henle: passive and
paracellular (favorable electrochemical
gradient)
• Distal nephron: active and transcellular
• Ca+2 diffuses down electrochemical gradient
at luminal membrane
• Transported across basolateral membrane by
Na+-Ca+2 antiporter and Ca+2 ATPase
Factors affecting renal Ca+2
reabsorption
• Proximal tubule: Ca+2
reabsorption parallels Na+ and
water reabsorption
• Increased by volume depletion
• Decreased by volume expansion
Factors affecting renal Ca+2
reabsorption
• Increased serum Pi stimulates PTH
release (via decreased serum Ca+2)
• PTH increases Ca+2 reabsorption and
decreases Pi reabsorption in kidney
• Allows retention of Ca+2 but excretion
of Pi mobilized from bone by PTH and
absorbed from gut via calcitriol
Factors affecting renal Ca+2
reabsorption
• Metabolic acidosis stimulates
Ca+2 reabsorption in distal
tubules
• Metabolic alkalosis inhibits
Ca+2 reabsorption in distal
tubules
Renal handling of phosphate
• Filtered by glomeruli and
reabsorbed by tubules but not
secreted
• 75-95% of the filtered load of Pi is
reabsorbed in the proximal tubule
by co-transport with Na+
Renal handling of phosphate
• Pi-rich meal will increase serum Pi
and filtered load with consequent
increase in urinary Pi excretion
• Increased serum Pi will increase PTH
(via decreased serum Ca+2) which will
decrease Tmax for Pi reabsorption in
proximal tubule and increase urinary
Pi excretion