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Dr J. Mohan
April 07 & 11, 2011 1
Renal Physiology
April, 2011
J. Mohan, PhD.
Lecturer,
Physiology Unit,
Faculty of Medical Sciences,
U.W.I., St Augustine.
Office : Room 105, Physiology Unit.
References:
�Koeppen B.E. & Stanton B.A. (2010). Berne & Levy Physiology.
6th Edition. Mosby, Elsevier.
�Marieb, E. & Hoehn, K. (2010). Human Anatomy & Physiology.
8th Edition, Pearson, Benjamin Cummings.
�Stanfield, C.L. & Germann W.J. (2008). Principles of Human
Physiology. 3rd Edition, Pearson, Benjamin Cummings.
�Hall, J.E. (2011). Guyton and Hall Textbook of Medical
Physiology. 12th Edition, Elsevier, Saunders.
Dr J. Mohan
April 07 & 11, 2011 2
Physiology Objectives
1. Give an account of the main cellular mechanisms involved in
the modification of the glomerular filtrate as it flows through
the tubular segments of the nephron (transport and tubular
re-absorption of ions, organic solutes and water).
2. Summarise the events related to re-absorption of sodium
ions and water throughout the nephron.
Today’s Topics
• Solute and water transport along the nephron.
– Proximal Tubule
• Na+ Reabsorption.
• Water Reabsorption.
• Protein Reabsorption.
• Secretion of Organic Anions & Cations.
– Henle’s Loop
– Distal Tubule & Collecting Duct
• Regulation of NaCl & H20 Reabsorption
Dr J. Mohan
April 07 & 11, 2011 3
Mechanisms of Urine Formation
• Urine formation
and adjustment of
blood composition
involves three
major processes
– Glomerular
filtration
– Tubular
reabsorption
– Secretion
Figure 25.10; Marieb & Hoehn, 2010
Solute and Water Transport along the Nephron
• Filtered at the glomeruli : ~ 180 L/day of essentially
protein-free fluid
• BUT < 1% of the filtered H20 & NaCl, and variable
amounts of other solutes are excreted in urine
Table 33.1, Koeppen & Stanton, 2010
Dr J. Mohan
April 07 & 11, 2011 4
Solute and Water Transport along the
Nephron
• reabsorption & secretion = important processes by which �renal tubules modulate the volume & composition of urine �precise control of volume, osmolality & pH of the ECF & ICF
• mediated by transport proteins in cell membranes of the nephron
• genetic & acquired defects in transport proteins � kidney diseases + many transport proteins � important drug targets
Proximal Tubule
• reabsorbs :
– approximately 67% of filtered water, Na+, Cl-, K+, and
other solutes
– virtually all the glucose & amino acids filtered by the
glomerulus
• reabsorption of every substance, including water, is linked to
the operation of Na+,K+-ATPase in the basolateral membrane
of PT
Dr J. Mohan
April 07 & 11, 2011 5
Na+ Reabsorption in 1st half of PT
Figure 33.1, Koeppen & Stanton, 2010
Na+ Reabsorption in 1st half of PT
• Ist half of PT
• Na+ entry to PT cell coupled to exit of H+ and entry of
HCO3-
– Na-H+ anti-port• active transport of Na+ at basolateral membrane via
Na+,K+-ATPase � Na+ enters cell & H+ leaves at
apical membrane
– HCO3- transporters
• CO2 + H2O ↔ H2CO3 ↔ HCO3- + H+
• HCO3- leaves the cell at basolateral membrane
Dr J. Mohan
April 07 & 11, 2011 6
Na+ Reabsorption in 1st half of PT
• Ist half of PT
• Na+ entry to PT cell coupled to entry of organic solutes
– Na+ enters proximal cells via several symportermechanisms, including Na+-glucose, Na+-amino acid, Na+-Pi, & Na+-lactate
– glucose and other organic solutes that enter the cell with Na+ leave the cell across the basolateral membrane via passive transport mechanisms
– Na+-glucose symporter• active tranport of Na+ at basolateral membrane via Na+/K+-
ATPase�• Na+ enters PT cell at apical membrane with glucose • glucose leave the cell at basolateral membrane
Na+ Reabsorption in 1st half of PT
Summary
• reabsorption of Na+ in the first half of the PT is coupled to
that of HCO3- and a number of organic molecules
• reabsorption of Na+ - HCO3 & Na+ - organic solutes across
the PT� transtubular osmotic gradient � driving force for the
passive reabsorption of water by osmosis
• more water than Cl- is reabsorbed in the first half of the PT,
the [Cl-] in tubular fluid rises along the length of the PT
Dr J. Mohan
April 07 & 11, 2011 7
Na+ Reabsorption in 2nd half of PT
Figure 33.3, Koeppen & Stanton, 2010
Na+ Reabsorption in 2nd half of PT
2nd half PT
• Na+ is mainly reabsorbed with Cl- across transcellular and
paracellular pathways
• Transcellular
– Na+ enters the cell across the apical membrane primarily via the parallel operation of an Na+-H+ antiporter and one or more Cl - - anion antiporters
– because the secreted H+ and anion combine in the tubular fluid and reenter the cell, operation of the Na+-H+ and Cl- -anion anti-porters is equivalent to uptake of NaClfrom tubular fluid into the cell
–Na+ leaves the cell via Na+,K+-ATPase, and Cl- leaves the cell and enters the blood via a K+-Cl- symporter in the basolateral membrane
Dr J. Mohan
April 07 & 11, 2011 8
Na+ Reabsorption in 2nd half of PT
• Paracellular
• paracellular NaCl reabsorption occurs because the rise in [Cl-]
in tubule fluid in the first half of the proximal tubule creates a
[Cl-] gradient (140 mEq/L in the tubule lumen and 105 mEq/L
in the interstitium)
• concentration gradient favors diffusion of Cl- from the tubular
lumen across the tight junctions into the lateral intercellular
space
• movement of negatively charged Cl- results in the tubular fluid
becoming positively charged relative to blood � positive
transepithelial voltage causes the diffusion of positively
charged Na+ out of the tubular fluid across the tight junction
into blood
Na+ Reabsorption in 2nd half of PT
• in the 2nd half of the proximal tubule, some Na+ and Cl- are
reabsorbed across the tight junctions via passive diffusion
• reabsorption of NaCl establishes a transtubular osmotic
gradient that provides the driving force for the passive
reabsorption of water by osmosis
Dr J. Mohan
April 07 & 11, 2011 9
Na+ Reabsorption in PT
Summary
• reabsorption of Na+ by different mechanisms in the 1st & 2nd halves
of the PT
• in the 1st half of the PT reabsorption of Na+ is coupled to that of
HCO3- and a number of organic molecules (transcellular)
• in the 2nd half of PT , Na+ is mainly reabsorbed with Cl- across
transcellular and paracellular pathways
• approximately 67% of the NaCl filtered each day is reabsorbed in
the PT
• of this, two thirds moves across the transcellular pathway, whereas
the remaining third moves across the paracellular pathway
Water Reabsorption
• PT reabsorbs 67% of filtered water
Table 33.5, Koeppen & Stanton, 2010
Dr J. Mohan
April 07 & 11, 2011 10
Water Reabsorption
Figure 33.4, Koeppen & Stanton, 2010
Water Reabsorption
• driving force for H20 reabsorption
– transtubular osmotic gradient established by reabsorptionof solute (e.g., NaCl, Na+-glucose)
– reabsorption of Na+ along with organic solutes, HCO3-& Cl- from tubular fluid � lateral intercellular spaces ��osmolality of the tubular fluid and � � the osmolality of the lateral intercellular space
• PT- highly permeable to water � water reabsorbed via osmosis
– apical & basolateral membranes of PT cells express aquaporin water channels � water primarily reabsorbed across PT cells
– some water also reabsorbed across tight junctions
Dr J. Mohan
April 07 & 11, 2011 11
Water Reabsorption
• accumulation of fluid and solutes within the lateral intercellular
space �� hydrostatic pressure in this compartment � forces
fluid and solutes into the capillaries
• some solutes, especially K+ & Ca 2+ are dissolved in the
reabsorbed fluid, and so are reabsorbed by the process of
solvent drag (across tight junction)
• reabsorption of virtually all organic solutes, Cl- and other ions,
and water is coupled to Na+ reabsorption
• therefore, changes in Na+ reabsorption influence the
reabsorption of water and other solutes by the proximal tubule
Protein Reabsorption
• peptide hormones, small proteins & small amounts of large
proteins e.g. albumin are filtered by the glomerulus
• only a small percentage of proteins cross the glomerulus and
enter Bowman's space (i.e., the concentration of proteins in
the glomerular ultrafiltrate is only 40 mg/L)
• BUT, the amount of protein filtered per day is significant
because GFR is so high:
• Filtered Protein = GFR X [Protein] in ultrafiltrate
= 180L/day X 40 mg/L
= 7200 mg/day or 7.2 g/day
Dr J. Mohan
April 07 & 11, 2011 12
Protein Reabsorption
• proteins undergo endocytosis either intact or after being
partially degraded by enzymes on the surface of proximal
tubule cells
• inside the cell, enzymes digest proteins � amino acids �
leave the cell across the basolateral membrane by transport
proteins and are returned to the blood
• normally, this mechanism reabsorbs virtually all the proteins
filtered, and hence the urine is essentially protein free
• however, because the mechanism is easily saturated, an
increase in filtered proteins ( as could result from disruption of
the glomerular filtration barrier) causes proteinuria
(appearance of protein in urine)
Secretion of Organic Anions and Organic
Cations
• PT cells secrete organic cations & organic anions (end
products of metabolism that circulate in plasma)
• important in limiting the body's exposure to toxic compounds
derived from endogenous and exogenous sources
Tables 33.6 & 33-7, Koeppen & Stanton, 2010
Dr J. Mohan
April 07 & 11, 2011 13
Secretion of Organic Anions and Organic
Cations
• exogenous organic compounds e.g. drugs & toxic chemicals
• many of these organic compounds can be bound to plasma
proteins and are not readily filtered � not eliminated from the
body via excretion after filtration alone
• secreted from the peritubular capillary � tubular fluid
• substances removed from plasma by both filtration &
secretion
Mechanisms of organic anion (OA-)
transport across the PT
Figure 33.5, Koeppen & Stanton, 2010
Dr J. Mohan
April 07 & 11, 2011 14
• Basolateral membrane
– Na+/K+ATPase
– α-KG inside the cells via metabolism of glutamate and by an Na+-α-KG
symporter (i.e., a Na+-dicarboxylate transporter [NaDC])
– OA- -α-KG antiporter mechanisms : OAT1 & OAT3 (take up OA-s in
exchange for α-ketoglutarate (α-KG))
• resulting high intracellular concentration of OA- provides a driving force for
exit of OA- across the apical membrane membrane into tubular fluid
• Apical membrane
– OA-s are transported across the apical membrane by OAT4 & by MRP2
(multidrug resistance-associated protein 2)
Mechanisms of organic anion (OA-)
transport across the PT
Mechanisms of organic cation (OC+)
transport across the PT
Figure 33.6, Koeppen & Stanton, 2010
Dr J. Mohan
April 07 & 11, 2011 15
• Basolateral membrane
– Na+/K+ATPase– 4 pathways : passive diffusion & 3 uniporters (OCT1, OCT2, &
OCT3)
– � OC+s are transported into PT cells across the basolateralmembrane by three related transport proteins (OCT1, OCT2, and OCT3) + diffusion
– � OC+s are taken up into the cell driven by cell negative potential difference
• Apical membrane
– OC+s leave the cell across the apical membrane in exchange for H+ by 2 OC+ - H+ antiporters (OCTN1, OCTN2 & MDR1)
Mechanisms of organic cation (OC+)
transport across the PT
Today’s Topics
• Solute and water transport along the nephron.
– Proximal Tubule
• Na+ Reabsorption.
• Water Reabsorption.
• Protein Reabsorption.
• Secretion of Organic Anions & Cations.
– Henle’s Loop
– DCT & Collecting Duct
• Regulation of NaCl & H20 Reabsorption
Dr J. Mohan
April 07 & 11, 2011 16
Henle's Loop
• Henle's loop (LoH) reabsorbs approximately 25% of the
filtered NaCl and 15% of the filtered water (See Tables 33-4 &
33-5)
– thin ascending and thick ascending limbs of LoH
• reabsorption of NaCl
• impermeable to water
– descending thin limb
• water reabsorption via AQP1 water channels
• Ca2+ & HCO3- are also reabsorbed in the LoH
Henle's Loop
• thin ascending limb reabsorbs NaCl by a passive mechanism
• reabsorption of water, but not NaCl, in the descending thin
limb increases [NaCl] in the tubule fluid entering the thin
ascending limb
• as the NaCl-rich fluid moves toward the cortex, NaCl diffuses
out of the tubule fluid across the thin ascending limb into the
medullary interstitial fluid, down a concentration gradient
directed from the tubule fluid to the interstitium
Dr J. Mohan
April 07 & 11, 2011 17
Mechanisms of solute transport across thick
ascending limb of LoH
Figure 33.7, Koeppen & Stanton, 2010
• Basolateral membrane
– Na+/K+ATPase
– K+ - Cl- symporter
– HCO3- ?
• Apical membrane
– 1Na+-1K+-2Cl- symporter (NKCC2)
– K+ channel
– Na+-H+ antiporter
Mechanisms of solute transport across thick
ascending limb of LoH
Dr J. Mohan
April 07 & 11, 2011 18
• increased NaCl transport by the thick ascending limb
increases the magnitude of the positive voltage in the lumen
• this voltage is an important driving force for the reabsorption
of several cations, including Na+, K+, Mg2+, & Ca2+, across
the paracellular pathway
Mechanisms of solute transport across
Henle's Loop
Henle's Loop
Summary
• NaCl reabsorption across the thick ascending limb occurs via
the transcellular and paracellular pathways
• Fifty percent of NaCl reabsorption is transcellular and 50% is
paracellular
• Because the thick ascending limb does not reabsorb water,
reabsorption of NaCl and other solutes reduces the osmolality
of tubular fluid to less than 150 mOsm/kg H2O : "diluting
segment"
Dr J. Mohan
April 07 & 11, 2011 19
Today’s Topics
• Solute and water transport along the nephron.
– Proximal Tubule
• Na+ Reabsorption.
• Water Reabsorption.
• Protein Reabsorption.
• Secretion of Organic Anions & Cations.
– Henle’s Loop
– DCT & Collecting Duct
• Regulation of NaCl & H20 Reabsorption
Distal Tubule and Collecting Duct
• The distal tubule and collecting duct :
– reabsorb approximately 8% of the filtered NaCl
– secrete variable amounts of K+ & H+
– reabsorb a variable amount of water (≈8% to 17%)
(See Tables 33-4 & 33-5)
Dr J. Mohan
April 07 & 11, 2011 20
Mechanism for reabsorption of Na+ & Cl- in
the early segment of the DT
Figure 33.8, Koeppen & Stanton, 2010
Distal Tubule and Collecting Duct
• Early DT
– reabsorbs Na+, Cl- & Ca++
– impermeable to water
• Basolateral membrane
– Na+/K+ATPase– Cl- channels
• Apical membrane
– Na+Cl- symporter
• dilution of tubular fluid begins in the thick ascending limb and
continues in the early segment of the DT
Dr J. Mohan
April 07 & 11, 2011 21
Distal Tubule and Collecting Duct
• Late DT & CD
– principal cells
• reabsorb NaCl & water and secrete K+
– intercalated cells
• secrete either H+ or HCO3- ( acid-base balance)
• reabsorb K+
Mechanisms of transport in the
late DT & CD
Cl-
Figure 33.9, Koeppen & Stanton, 2010
Dr J. Mohan
April 07 & 11, 2011 22
Mechanisms of transport in Principal Cells
Principal cells
• Basolateral membrane
– Na+,K+-ATPase
– K+ channels
– AQP 3&4
• Apical membrane
– epithelial Na+-selective channels (ENaCs)
– K+ channels
– AQP2
• Cl- reabsorbtion
– reabsorption of Na+ generates a negative luminal voltage
across the late DT & CD, which provides the driving force
for reabsorption of Cl- across the paracellular pathway
• H20 reabsorbtion
– water reabsorption is mediated by the AQP2 water
channel located in the apical plasma membrane & by
AQP3 and AQP4 located in the basolateral membrane of
principal cells
– in the presence of antidiuretic hormone (ADH), water is
reabsorbed
– in the absence of ADH, the DT & CD reabsorb little water
Mechanisms of transport in Principal Cells
Dr J. Mohan
April 07 & 11, 2011 23
• K+ secretion
– K+ is secreted from blood into tubular fluid by principal cells in two steps :
– (1) uptake of K+ across the basolateral membrane is mediated by the action of Na+,K+-ATPase
– (2) K+ leaves the cell via passive diffusion
• K+ channels
• K+ diffuses down its concentration gradient through apical cell membrane K+ channels into tubular fluid
• although the negative potential inside the cells tends to retainK+ within the cell, the electrochemical gradient across the apical membrane favors secretion of K+ from the cell into tubular fluid
Mechanisms of transport in Principal Cells
Mechanisms of transport in the
late DT & CD
Cl-
Figure 33.9, Koeppen & Stanton, 2010
Dr J. Mohan
April 07 & 11, 2011 24
• Intercalated cell
– Basolateral membrane
• HCO3- (passive diffusion)
– Apical membrane
• H+ leaves the cell
• H+-K+-ATPase mediates K+ reabsorbtion
Mechanisms of transport in Intercalated
Cells
Today’s Topics
• Solute and water transport along the nephron.
– Proximal Tubule
• Na+ Reabsorption.
• Water Reabsorption.
• Protein Reabsorption.
• Secretion of Organic Anions & Cations.
– Henle’s Loop
– DCT & Collecting Duct
• Regulation of NaCl & H20 Reabsorption
Dr J. Mohan
April 07 & 11, 2011 25
Regulation of NaCl & Water Reabsorption
NaCl reabsorption
• hormones
– angiotensin II, aldosterone, NE, Epi, natriuretic peptides,
and uroguanylin, dopamine & adrenomedullin
• Starling forces
• Glomerulotubular balance
H20
• ADH (direct)
Regulation of NaCl & Water Reabsorption
NaCl reabsorption
Angiotensin II
• Major Stimulus
– � renin
• Site of Action
– PT, thick ALoH, DT/CD
• Effect on Transport
– � reabsorption of NaCl & H20
Dr J. Mohan
April 07 & 11, 2011 26
Regulation of NaCl and Water Reabsorption
NaCl reabsorption
Aldosterone
• Major Stimulus
– � AgII, � plasma [K+]
• Site of Action
– thick ALoH, DT/CD
• Effect on Transport
– � reabsorption of NaCl & H20
– � secretion of K+
Mechanisms for Reabsorption of NaCl by
Aldosterone
• early distal tubule
– � # of the Na+-Cl- symporter
• principal cells – DT/CD
– (1) � the amount of Na+,K+-ATPase in the basolateral
membrane
– (2) � expression of the Na+ channel (ENaC) in the apical
cell membrane
– (3) � Sgk1 (serum glucocorticoid-stimulated kinase) levels
� � the expression of ENaC in the apical cell membrane
– (4) stimulating CAP1 (channel-activating protease, also
called "prostatin"), a serine protease that directly activates
ENaCs by proteolysis
Dr J. Mohan
April 07 & 11, 2011 27
Mechanisms for Reabsorption of NaCl by
Aldosterone
• reabsorption of Na+ � negative luminal voltage across the
distal tubule and collecting duct.
• this negative voltage in the lumen provides the
electrochemical driving force for reabsorption of Cl- across the
tight junctions (i.e., paracellular pathway) in the distal tubule
and collecting duct
• through its stimulation of NaCl reabsorption in the collecting
duct, aldosterone also indirectly increases water reabsorption
by this nephron segment
Mechanisms for Reabsorption of NaCl by
Natriuretic peptides (ANP & BNP &
urodilatin)• Major Stimulus
– � ECFV; � BP
• Site of Action – Medullary CD
• Effects– � reabsorption of NaCl & H20� � excretion– � ADH-stimulated water reabsorption across the collecting
duct– � secretion of ADH from the posterior pituitary
• actions of ANP & BNP mediated by the activation of membrane-bound guanylyl cyclase receptors � � cGMP
• Urodilatin > profound natriuresis & diuresis than ANP > profound natriuresis & diuresis than BNP
Dr J. Mohan
April 07 & 11, 2011 28
Mechanisms for Reabsorption of NaCl by
NE & Epi
• Major Stimulus – � ECFV; � BP
• Site of Action – PT, thickALoH, DT/CD
• Effects– � reabsorption of NaCl & H20
Mechanisms for Reabsorption of H20 by
ADH
• Major Stimulus – � Posm; � ECFV
• Site of Action – DT/CD
• Effects– � reabsorption of H20
Dr J. Mohan
April 07 & 11, 2011 29
Mechanisms for Reabsorption of NaCl &
H20 by Starling’s forces
Figure 33.9, Koeppen & Stanton, 2010
• Starling forces that favor
movement from the
interstitium into the
peritubular capillaries are
πpc & Pi
• the opposing Starling forces
are πi & Ppc
• major Starling force driving
reabsorbtion = π pc (high
oncotic pressure of the
peritubular capillary blood)
Mechanisms for Reabsorption of NaCl &
H20 by Starling forces
• Recall : glomerular filtration � �
the [protein ] and π of glomerular
capillaries; this blood leaves
glomerular capillaries � efferent
arterioles � peritubular
capillaries
Dr J. Mohan
April 07 & 11, 2011 30
• therefore, peritubular capillary oncotic pressure (πpc) is
partially determined by the rate of formation of the glomerular
ultrafiltrate
• E.g. � in GFR, at constant RPF in the afferent arteriole � �
[plasma proteins] in the efferent arteriole & peritubular
capillary � � π pc
• πpc is directly related to the filtration fraction :
FF = GFR
RPF
• � FF resulting from a � GFR, at constant RPF � � π pc �
� net reabsorption of solute and water across the PT
Mechanisms for Reabsorption of NaCl &
H20 by Starling forces
Glomerulotubular (G-T) balance
• major mechanism for regulating solute & water reabsorption
by the PT
• describes the balance between filtration (glomerulus) and
reabsorbtion (PT)
• depends on Starling forces
G-T Balance
Dr J. Mohan
April 07 & 11, 2011 31
• spontaneous changes in GFR markedly alter the filtered load
of Na+ (filtered load = GFR × [Na+] in the filtered fluid)
• e.g. � GFR � � filtered Na+ � � urinary excretion of Na+
� disturbed Na+ balance, if Na+ reabsorption is not rapidly
adjusted
• however, spontaneous changes in GFR do not alter Na+
excretion in urine or Na+ balance because of the
phenomenon of G-T balance
G-T Balance
• when body Na+ balance is normal (i.e., ECF volume is
normal), G-T balance refers to the fact that reabsorption of
Na+ & water increases in proportion to the increase in GFR
and filtered load of Na+
• therefore, a constant fraction of the filtered Na+ and water is
reabsorbed from the PT despite variations in GFR
• the net result of G-T balance is to reduce the impact of
changes in GFR on the amount of Na+ & water excreted in
urine
G-T Balance
Dr J. Mohan
April 07 & 11, 2011 32
• 2nd mechanism
– increase in the filtered load of glucose & amino acids �� reabsorption of Na+ & H20
– reabsorption of Na+ in the 1st half of the proximal tubule is coupled to that of glucose & amino acids
–the rate of Na+ reabsorption therefore partially depends on the filtered load of glucose & amino acids
– as the GFR and filtered load of glucose & amino acids increase, reabsorption of Na+ & water also rises
G-T Balance
Summary of G-T balance
• � in GFR �
– � FF � � π pc � � solute & H20 reabsorbtion in PT
– � filtered glucose & aa � � reabsorbtion Na+ in PT
G-T Balance
Dr J. Mohan
April 07 & 11, 2011 33
Summary of GT-balance
• � in GFR �
– � FF � � π pc � � reabsorbtion in PT
– � filtered glucose & aa � � reabsorbtion Na+ in PT
• Proportionality of filtration and reabsorbtion is maintained i.e.
there is glomerular tubular balance
• Na+ homeostasis (and ECF volume and blood pressure)
G-T Balance
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