renal physiology april, 2011 - medscistudents 1102/renal lecture 2... · april 07 & 11, 2011 1...

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


• 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


• 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


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



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


• 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


• 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


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


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-)


Mechanisms of organic cation (OC+)



Dr J. Mohan

April 07 & 11, 2011 15


– 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+)


Today’s Topics


– Proximal Tubule





– Henle’s Loop

– DCT & Collecting Duct


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



– 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


– Proximal Tubule





– Henle’s Loop



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



• Early DT

– reabsorbs Na+, Cl- & Ca++

– impermeable to water


– 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


• 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-


Dr J. Mohan

April 07 & 11, 2011 22

Mechanisms of transport in Principal Cells

Principal cells


– 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


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 the

late DT & CD

Cl-


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


– Proximal Tubule





– Henle’s Loop



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


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


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


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


• 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)


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


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

renal physiology april, 2011 - medscistudents 1102/renal lecture 2... · april 07 & 11, 2011 1...

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