3.

01a

November 04, 2015

Fernando P. Solidum, MD., DPBA

TOPIC OUTLINE
I.
Functions of the Kidney
II. Structure of the Kidney
a.
Layers of the Kidney
b.
Other Parts
III. Nephron
a.
Parts of the Nephron
b.
Vasa Recta
IV. Ultrafiltration
V. Filtration Barrier
VI. Mesangium
VII. Extraglomerular Mesangial Cells
VIII. Ultrastructure of the Juxtaglomerular Apparatus
IX. Assessment of Renal Function
a.
Inulin Clearance
b.
Creatinine Clearance
c.
Filtration Fraction
X. Glomerular Filtration Rate
XI. Renal Blood Flow
XII. Mechanisms of Autoregulation
XIII. Regulation of RBF and GFR
XIV. General Principles of Transepithelial Solute and Water
Transport

Minor Calyx: collects urine from each papillar

Major Calyx: combination of minor calyces
Pelvis: combination of major calyces; represents the upper and
expanded region of the ureter
Ureter: carries urine to bladder

Fluids from glomerulus....................................................................ultrafiltrate
Fluids in nephron segments.........................................................tubular fluid
Fluids that leave the collecting ducts.......................................................urine

FUNCTIONS OF THE KIDNEY

Regulates:
o
Body fluid osmolality and volumes
!
In dehydration compensation is producing scanty urine
!
Kidney can detect change in concentration of solutes in the
body
o
Electrolyte balance
!
In the proximal tubule 67% of electrolytes are filtered and
reabsorbed
o
Acid-base balance
!
pH adjustment through pulmonary and renal mechanisms
!
3rd line of defense in acid-base balance
Excretes metabolic products and foreign substances from fat and
carbohydrate metabolism
Produces and secretes hormones
o
This is the most important function
o
Erythropoietin which is the precursor of RBC production
o
Renin for RAAS activation (precursor of Angiotensin II)

Body Osmolality 300 mOsm will be used for consistency
osmolality = dehydration, ADH secretion
osmolality = fluid overload, ADH secretion

STRUCTURE OF THE KIDNEY

A. Layers of the Kidney
1. Cortex
o
Outermost layer; where glomerulus can be found
2. Medulla
o
Innermost layer; where most absorption takes place
3. Pelvis
o
Junction between kidneys and ureters

B. Other parts

Renal Pyramids: conical masses in the medulla

Papilla: apex of the pyramid, its base originates at the

corticomedullary border; lies within a minor calyx

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RENAL PHYSIOLOGY I

Blood Supply:
o
Blood flow is equivalent to about 25% of CO (1.25L) in resting
individuals
o Renal Artery ! Interlobar Artery ! Arcuate Artery !
Interlobular Artery ! Afferent Arteriole ! Glomerular
Capillaries ! Efferent Arteriole ! Peritubular Capillaries (2nd
capillary network which supply blood to nephron)

NEPHRON
Basic functional unit of the kidney
Each kidney contains about 1.2 million nephrons
Can reach outer medulla and others can go as far as inner medulla
Have varied strength to dilute or concentrate tubular fluid
Classified based on their locations:
o
Cortical Nephrons
!
Its loop of Henle reaches the outer medulla (outer medulla
ang pinakamalalim na pwede nyang maabot)
!
Vascular supply: Peritubular Arteries
o
Juxtamedullary Nephrons
!
Covers the inner medulla of the kidney and its loop of
Henle runs side by side the vasa recta and deep medulla
(mas malalim ang naabot ng loop of Henle nya compared
kay cortical)
!
Vascular Supply: Vasa Recta

Vasa Recta receives H2O and other solutes and

returns it back to circulation; dilutes/concentrates
urine; countercurrent exchangers

A. Parts of the Nephron
1. Renal Corpuscle

Consist of:
a.
Glomerulus

3.01a

Renal Physiology I

Network of capillaries supplied by the afferent and
efferent arterioles
High hydrostatic pressure (60mmHg)
Has three layers (will be discussed later in filtration
barrier):
!
Capillary Endolthelium
!
Basement Membrane
!
Podocytes
Bowmans Space
Space between visceral and parietal layer that
separates Bowmans capsule and glomerulus.
Ultrafiltrate ang tawag kapag andito pa lang ang
fluid. Okay?!
Bowmans Capsule
where the filtrate goes after passing the glomerulus.
-

b.

c.

2.

3.

Proximal Tubule

67% of Na, Cl and H20 and 95% of HCO3- and proteins that
enters the tubules is being handled by proximal tubule
(absorption / filtration)

Presence of brush border that increases surface area for

tubular reabsorption

Contains very high number of mitochondria

ISOSMOTIC and H2O PERMEABLE

Lies in the cortex of the kidney and drains into the Loop of
Henle
Loop of Henle

Involved in the dilution and concentration of tubular fluid

Countercurrent multiplier

NO BRUSH BORDERS

Poorly developed apical and basolateral membranes and few

mitochondria

Different parts of the loop have different permeabilities and

functions:
o
Thin descending limb
Ends in hairpin turn
Concentrating segment: permeable to water so it
tends to lose water while solutes remain
Outer to inner medulla
o
Thin ascending limb
Permeable to water
o
Thick ascending limb
Starting to regain mitochondria (there is active
transport of NaCl and other solutes as it approaches
the distal convoluted tubules)
Outer medulla to cortex
Macula Densa
!
short segment of thick ascending limb

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Renal

!
4.

5.

Part of the Juxtaglomerular apparatus that is

important
in
autoregulating
NaCl
concentration

Distal Tubule

Increased number of mitochondria

Aids in active transport of NaCl and other solutes

Cortical Collecting Ducts

Initially impermeable to water

ADH changes it to permeable by morphologically activating

aquaporins

Note: The 2nd half of distal convoluted tubule and the rest of the
collecting ducts contain specialized that act primarily in K+,
HCO3-, and H+ transport; they are:
o
Principal cells
For Na absorption/excretion
8% in number of all specialized cells
o
Intercalated cells
For H+ and HCO3- absorption/excretion
Acid- base regulation

Vasa Recta
Forms capillary networks that surrounds the collecting ducts and
the ascending limbs of Henle
Conveys Oxygen to the nephron segments
Supplies nutrients to nephron segments
Acts as a pathway for reabsorbed water and solutes to the
circulatory system
Concentrates and dilutes urine

ULTRAFILTRATION

Refers to the passive movement of an essentially protein-free fluid

from the glomerular capillaries into Bowmans space.

FILTRATION BARRIER

3.01a

Renal Physiology I

Not all of the blood that passes through the glomerulus is filtered.
The structures that act as filtration barriers are:
1. Capillary Endothelium
!
Fenestrated, freely permeable to water
!
With negatively-charged glycoproteins on its surface
!
Synthesize vasoactive substances like Nitric oxide
(vasodilator), and endothelin (vasoconstrictor)
!
Negatively charged solutes will not be filtered
2. Basement Membrane
!
Also negatively charged proteins
!
Charge selective filter
!
Cationic molecules are filtered more readily than
anionic molecules for molecules with an effective
molecular radius between 20 and 40
3. Foot Processes of Podocytes
!
Endocytic properties
!
Have long, finger-like processes that completely encircle
the outer surface of the capillaries
!
Interdigitate to cover the gaps between the basement
membrane
!
Separated by gaps called filtration slits
!
PODOCALYXIN
Negatively charged membrane glycoprotein in
podocytes
Keep the filtration slits open

Notes:

Exceptions on the negatively charged solutes which can cross the
filtration barrier

1. Small radius size

2. Hydrostatic pressure in the capillaries

In cases of renal disease (example glomerulonephritis), the filtration

barrier:
- Inflammation causes destruction of filtration barrier

- Flattening of the 3 layers

- Widening of filtration slits everything can cross

- Urinalysis: presence of proteins, glucose, blood, RBC

ULTRASTRUCTURE OF THE
JUXTAGLOMERULAR APPARATUS

Important in tubuloglumerular feedback mechanism

Involved In autoregulation of GFR and renal blood flow
Regulate blood flow in arterioles
Controls the amount of blood going to the glomerulus
Has three components:
1. MACULA DENSA of the THICK ASCENDING LIMB
!
Passes through the AA and EA of the same nephron
!
Contacts with mesangial cells and granular cells derived
from metaphroc mesenchymal cells which manufacture,
store and release renin
!
Function as chemoreceptor or osmoreceptor
2. EXTRAGLOMERULAR MESANGIAL CELLS
!
Mesangial cells appear to control the glomerular filtration
rate
3. RENIN-PRODUCING GRANULAR CELLS of the AFFERENT
ARTERIOLES
!
Modified smooth muscle that store, manufacture and
release renin
!
Act as a mechanoreceptor
!
Renin: involved in angiotensin II formation, secretion of
aldosterone

MESANGIUM

Structural support for the glomerular capillaries

Maintains the roundness of the glomerulus (structural support)
Possess smooth muscle properties
Consists of:
o
Mesangial cells
!
Similar to monocytes
!
Surround glomerular capillaries
!
Provide structural support to the glomerular capillaries
o
Mesangial matrix
Other functions:
o
Secrete the extracellular matrix
o
Surround glomerular capillaries
o
Exhibit phagocytic activity by removing macrophages
o
Secrete prostaglandins and proinflammatory cytokines
o
Influence GFR via regulating blood flow through the
glomerular capillaries or by altering the capillary surface area.

EXTRAGLOMERULAR MESANGIAL CELLS or LACIS

CELLS or GOORMAGTIGH CELLS

Notes:
If pressure in AA is , more blood is filtered in glomerulus
ultrafiltrate tubular fluid
Remember:
MD will sense if the fluid is matabang or maalat "will send
signal to EGM " EGM will send signal to AA if it will vasodilate
(if matabang) or will vasoconstrict (if maalat). After
vasodilation, there will be GFR and [NaCl]. After
vasoconstriction, there will be GFR and [NaCl].

ASSESSMENT OF RENAL FUNCTION

Mesangial cells outside the glomerulus

Exhibits phagocytic activity

MESANGIUM

3 of 13 Renal Physiology I [Witty trans group name]

Renal

There are 3 general processes which determines the amount of

substances that appears in the urine:
1.
Glomerular filtration
2.
Reabsorption of substances from tubular fluid
3.
Secretion of substances from blood to tubular fluid

Renal Clearance
A theoretical measurement of Glomerular Filtration Rate (GFR) and
Renal Blood Flow (RBF)
Based on Fick principle (mass balance or conservation of mass)

3.01a

Renal Physiology I

Inulin Clearance
Used to measure GFR
Inulin
o
Polymer of fructose
o
Neither reabsorbed nor metabolized
o
All inulin enetering the renal artery is not filtered at the
glomerulus; the rest return to the renal veins (only 15-20%
filtered)
o
Not produced by the body
o
Freely filtered across the glomerulus into the Bowmans space
o
Amount of Inulin filtered = Amount excreted

=
Input:
Red upper blood vessel = renal artery
Output: +
Blue lower blood vessel = renal vein
Yellow inferior bent vessel = renal pelvis + ureter

= +

Where:

= concentration of substance X in renal artery

= renal plasma flow rates in artery

= concentration of substance X in renal vein

= renal plasma flow rates in veins

= concentration of substance in urine

= urine flow rate

The equation means:
The amount of substance X that enters the kidney in the renal artery is
equal to the amount that leaves the kidney to the systemic circulation
and urine via the renal vein and urethra respectively.

However, clearance does not measure all these factors.

Clearance is the volume in which all substances has been removed and
excreted into urine per unit in time.

Considers only the rate at which a substance is excreted in the

urine.

Also determines if a substance is reabsorbed or secreted

Where:
= Glomerular Filtration Rate
= Urine concentration of Inulin
= Plasma concentration of Inulin
= Urine flow

Creatinine Clearance

Can also be used to measure GFR

Creatinine
o
by product of skeletal muscle creatine metabolism
o
Thought to be produced at a constant rate
o
Freely filtered across the glomerulus into Bowmans space
o
Amount of Creatinine filtered = Amount excreted
o

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Where:
= Glomerular Filtration Rate
= Urine concentration of Creatinine
= Plasma concentration of Creatinine
= Urine flow

Relationship between GFR and Creatinine

GFR = Plasma Creatinine

(because creatinine is
excreted)

GFR = Plasma Creatinine
(because creatinine is
retained)

= clearance

For any substance that is neither synthesized nor metabolized, the amount
that enters the kidneys is equal to the amount that leaves the kidneys in the
urine plus the amount that leaves the kidneys in the renal venous blood.

Glomerular Filtration Rate

Sum of the filtration rates and all functioning nephrons: index of

kidney functions

Fall in GFR: Kidney disease progress

Determines prognosis of disease

Normal values:
Males: 90 to 140 ml/min
Females: 80 to 125 ml/min

Factors to be considered to appropriately measure GFR
1.
Substance freely filtered across glomerulus into Bowmans
space
2.
Substance not be reabsorbed or secreted by the nephron
3.
Substance not be metabolized or produced by the kidney
4.
Substance itself does not alter GFR

Concerns in the use of Plasma Creatinine
1.
Not accurate
o
Renal tubules can secrete creatinine = overestimation of
GFR (kasi pwede pa ring maging part ng urine ang
creatinine)
2.
Creatinine production is not constant to all individuals
3.
A slight increase in serum creatinine would correspond to a
decrease in renal function from 100% of normal.

3.01a

Renal Physiology I

FILTRATION FRACTION
Filtration Fraction = GFR/RPF
Portion of the plasma that is filtered
60% of blood is plasma " will be filtered by the glomerulus
15 to 20% of plasma that enters the glomerulus is actually filtered
Remaining 80 to 85% continues to pass through the glomerulus to
the efferent arterioles to peritubular capillaries to the systemic
circulation

The reduced filtration rate for anionic molecules is explained by the

presence of negatively charged glycoproteins on the surface of all
components of the GFB (which repel similar charges)

If a substance is freely filterable in terms of size but is negatively charged,

how can it cross the filtration barrier?

With increased hydrostatic pressure

GLOMERULAR FILTRATION RATE

Normal GFR
o
Males: 90-140 ml/min
o
Females: 80-125 ml/min
o
180L/day of plasma filtered
o
After age 30, GFR declines but does not adversely affect the
kidneys functions

ULTRAFILTRATE
The 1st step in the formation of urine
Devoid of cellular elements (i.e. red and white blood cells and
platelets) and is protein free
Same composition with plasma
Starling forces drive ultrafiltrate across the glomerular capillaries
Changes in Starling forces alter the GFR
GFR (Glomerular Filtration Rate) and RPF (Renal Plasma Flow) are
normally held within very narrow ranges by autoregulation.

A. Determinants of Ultrafiltrate Composition

The structure of the Glomerular Filtration Barrier determines

composition of the plasma ultrafiltrate.
o
Capillary Endothelium
o
Basement Membrane
o
Filtration Slits (Podocytes)

GFB restricts the filtration of molecules on the basis of both SIZE

and ELECTRICAL CHARGE.
o
Size

20 = Filtered freely (wee!)

20 - 42 = Filtered to various degrees, depending on the

charge

> 42 = NOT FILTERED

o
Electrical Charge

Cations = readily filtered

Anions = restricted filtration due to the repulsion by the

negatively charged proteins present on the barrier (GFB)

B. Dynamics of Ultrafiltration

Forces responsible for glomerular filtration of plasma are the same

as those in all capillary beds (Starling Forces)

Ultrafiltration occurs because the Starling forces (i.e. hydrostatic

and oncotic pressure) drive fluid from the lumen of glomerular
capillaries, across the filtration barrier, and into the Bowmans
space
Glomerular capillaries "across GFB " Bowmans Space
A. Facilitates Filtration

As the size increases, filterability (ability to pass through the GFB)

decreases " inverse relationship
Not exceeding 42 , cations have greater filterability than anions.

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Reduction of the negative charges on the glomerular wall (GFB)

causes proteins to be filtered solely on the basis of their effective
molecular radius.

Glomerular Capillary Hydrostatic Pressure (PGC)

o
Promotes the movement of fluid from the glomerular
capillary into the Bowmans space
o
Decreases slightly along the length of the capillary
because of the resistance to flow along the length of the
capillary
o
Only force that favors filtration
o
Increased when there is increased blood flow in afferent
arterioles
o
Decreased when afferent arteriole is constricted
Oncotic Pressure in the Bowmans Space (BS)
o
Increases oncotic pressure in the Bowmans space can
facilitate filtration, but since the glomerular ultrafiltrate is
protein-free, and the oncotic pressure in the Bowmans
space is near zero therefore, GC Hydrostatic Pressure is
the only force that favors filtration.
o
Only in abnormal states where BS is increased that it can
contribute to filtration

3.01a

Renal Physiology I

o
o
o

Changes in afferent arteriolar resistance

a) resistance PGC GFR
b) resistance PGC GFR
Changes in efferent arteriolar resistance
a) resistance PGC GFR
b) resistance PGC GFR
Changes in renal arteriolar resistance
a) BP PGC GFR
b) BP PGC GFR

RENAL BLOOD FLOW (RBF)

At rest: 25% of CO (1.25L/min)
Functions:
1.
Indirectly determines the GFR
2.
Modifies the rate of solute and water reabsorption by the
proximal tubule
3.
Participates in the concentration and dilution of urine
4.
Delivers O2, nutrients, and hormones to the cells of the
nephron and returns CO2 and reabsorbed fluid and solutes to
the general circulation
5.
Delivers substrates for excretion in urine

Blood flow through any organ may be represented by the equation:

Q = P/R
Q = blood flow, P = mean arterial pressure minus venous pressure for that
organ, R = resistance to flow through that organ.

Accordingly, RBF is equal to the pressure difference between the

renal artery and the renal vein divided by renal vascular resistance.

B. Opposes Filtration

Hydrostatic Pressure in the Bowmans Space (PBS)

o
If this force is greater than the hydrostatic pressure in the GC,
it prevents filtration as it exerts greater force on the GFB in
relation to the force that PGC exerts " happens where there is
an obstruction somewhere along the tubules
Oncotic Pressure in the Glomerular Capillary (GC)
o
Increases along the length of the glomerular capillary, because
water is filtered and protein is retained in the glomerular
capillary, so the protein concentration in the capillary rises,
and GC increases

The afferent arteriole, efferent arteriole, and interlobular
artery are the major resistance vessels in the kidneys and thereby
determine the renal vascular resistance.

Net Ultrafiltration pressure (PUF):

o
o
o

Afferent end of glomerulus: 17 mmHg

Efferent end of glomerulus: 8 mmHg
PUF = PGC PBS GC

C. GFR Alteration

GFR is proportional to the sum of the Starling Forces that exist

across the capillaries multiplied by the ultrafiltration coefficient (Kf)
so that any change in the Starling forces changes GFR
GFR= Kf [(PGC - PBS) - (GC - BS)]
* The reflection coefficient for protein across the
glomerular capillary () = 1

Kf is the product of the intrinsic permeability of the glomerular

capillary and the glomerular surface area available for filtration

As Kf increases, GFR increases.

GFR can be altered by changing Kf or by changing any of the Starling

forces. From the equation above:
o
Changes in Kf: Kf GFR
o
Changes in PGC: PGC GFR
o
Changes in PBS: PBS GFR
o
Changes in GC: GC GFR
o
BS ~ 0

In normal individuals, the GFR is regulated mainly by changes in

afferent or efferent arteriolar resistance (which alters hydrostatic
pressure in the glomerular capillaries, PGC)
Changes in glomerular arteriolar resistance "alteration in PGC " GFR
Regulated

PGC is affected in three ways:

6 of 13 Renal Physiology I [Witty trans group name]

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Like most other organs, the kidneys regulate blood flow by adjusting
vascular resistance in response to changes in arterial pressure.
These adjustments are so precise that blood flow remains relatively
constant between 90 and 180 mmHg.
Relatively constant maintenance of RBF and GFR is achieved by
adjusting the vascular resistance, specifically the afferent arterioles
(AUTOREGULATION).

MECHANISMS OF AUTOREGULATION

Autoregulation is absent below 90 mmHg

Autoregulation of RBF and GFR changes slightly as arterial blood
pressure varies. It is not perfect, just like us.

3.01a

Renal Physiology I

GFR and RBF can be influenced by certain hormones, and by
changes in sympathetic nerve activity
If a significant amount of blood is lost, GFR and RBF decrease.
Two mechanisms are responsible for autoregulation of RBF and GFR
by regulating the tone of the afferent arteriole.

the macula densa cells " ATP and adenosine production and

I. Myogenic Mechanism

Pressure-sensitive mechanism

Related to intrinsic property of vascular smooth muscle: the

tendency to contract when stretched

In contrast, when GFR and NaCl concentration "less NaCl enters

release " vasodilation of afferent arterioles " normalize GFR and

RBF
The macula densa may release both vasoconstrictors and
vasodilators that oppose each others action at the level of the
afferent arteriole.
Effector substances produced by macula densa cells:
o
Adenosine = Vasoconstriction
o
Nitric Oxide (NO) = Vasodilation
o
Angiotensin II = Vasoconstriction

REGULATION OF RBF AND GFR

Major Hormones That Influence the GFR and RBF

II. Tubuloglomerular Feedback

How changes in afferent and efferent arteriolar resistance, mediated by

changes in these hormones modulate GFR and RBF:

NaCl concentration-dependent mechanism

At the cellular level:

When GFR " NaCl concentration in the tubular fluid at the macula
densa " more NaCl enters the macula densa cells" formation
and release of ATP and Adenosine" ATP binds to receptos on
extraglomerular mesangial cells" release vasoconstriction of
afferent arteriole " normalize GFR and RBF

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3.01a

Renal Physiology I

II. Hormonal Control of RBF and GFR
A. Angiotensin II

Through RAAS it is produced.

Constricts both afferent and efferent arterioles but efferent

arterioles are more sensitive to A-II.

RBF and GFR

Angiotensin Converting Enzyme (ACE) converts Angiotensin I to II.

It degrade and inactivate bradykinin

Changes in RBF

Constriction of either the afferent or efferent arteriole increase

resistance, and according to equation Q = P/R, if resistance (R)
increases , flow (Q) decreases
Dilation of either arteriole increases flow (i.e. RBF)

Changes in GFR
(A) Constriction of afferent arteriole( PGC)

Because less of the arterial pressure is transmitted to the

glomerulus thereby causing GFR.
(B) Constriction of efferent arteriole

In contrast, constriction of the efferent arteriole elevates PGC or

the hydrostatic pressure inside the glomerular capillary and
thus GFR.
(C) Dilation of efferent arteriole

PGC and thus GFR

(D) Dilation of afferent arteriole

PGC because more of the arterial pressure is transmitted to

the glomerulus, thereby increasing GFR
I. Sympathetic control of Renal Blood Flow (RBF)

The afferent and efferent arterioles are innervated by sympathetic

neurons; however, sympathetic tone is minimal when the volume
of extracellular fluid is normal

Sympathetic nerves release norepinephrine and dopamine, and

circulating epinephrine is secreted by the adrenal medulla

Dehydration or strong emotional stimuli (such as fear and pain)

activate sympathetic nerves, release vasoconstrictors and reduce
GFR and RBF

Low blood volume and blood pressure (haemorrhage) also

stimulates release of NE and Epi via baroreceptor reflex, leading to
decrease in GFR and RBF

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The figure shows how norepinephrine, epinephrine, and angiotensin II
act together to decrease RBF and GFR and thereby increase BP and
extracellular fluid volume, as would occur with haemorrhage.
B. Prostaglandin

No effect on RBF and GFR in healthy individuals

In pathological states, PGI1 and PGE2 are produced locally in the

kidneys. It RBF without changing GFR.

RBF by dampening the vasoconstrictor effects of sympathetic and

A-II

Prevents severe vasoconstriction and renal ischemia

C. Nitric Oxide

Endothelium-derived relaxing factor

Counteracts effects of A-II and catecholamines

Dilation of afferent and efferent arterioles

It decreases TPR and inhibited production of NO BP

D. Endothelin

Secreted by endothelial cells of renal vessels, mesangial cells, and

distal tubular cells in response to A-II, bradykinin, Epi and stretch

Profound Vasoconstriction of afferent and efferent arterioles "

RBF and GFR

3.01a

Renal Physiology I

E. Bradykinin

By-product of kininogen breakdown

Kallikrein cleaves kininogen "bradykinin " stimulates release of

NO and prostaglandins "vasodilation" RBF
F. Adenosine

Vasoconstriction of afferent and efferent arteriole

RBF and GFR

Tubuloglomerular feedback regulation

G. Atrial Natriuretic Peptide (ANP)

Vasodilation of afferent arteriole

Vasoconstrictor of efferent arteriole

Modest in GFR, no change in RBF

ANP secretion increases with hypertension and expansion of

extracellular fluid volume.

Transcellular Pathway

Traversing both the apical and basolateral membranes

Via (1) Passive or Facilitated Diffusion, (2) Active Transport, (3)

Solvent Drag

Na+,K+-ATPase (active transport) is found in the basolateral

membrane on almost all segments.
o
In the thick ascending limb, it is important in changing the
osmolarity of the medullary interstitium.

Any solute that is actively transported across an epithelium must be

transported via the transcellular pathway.

H. ATP

Dual effects on GFR and RBF

Constricts afferent arteriole and reduces RBF and GFR

May stimulate NO production and increase RBF and GFR

I. Glucocorticoids

Increases GFR and RBF

J. Histamine

Increases RBF without elevating GFR by decreasing resistance of

afferent and efferent arterioles.
K. Dopamine

Produced by proximal tubule and it increases RBF and inhibiting

renin secretion

















This figure shows examples of the interactions of endothelial cells with
smooth muscle and mesangial cells.

GENERAL PRINCIPLES OF TRANSEPITHELIAL SOLUTE

AND WATER TRANSPORT

Paracellular Pathway

Via tight junctions in between cells

o
Proximal tubule and descending limb: loose tight junctions
o
Thick ascending limb: tight tight junctions (practically
impermeable to H2O)

Passive in nature (driving force: concentration or voltage gradient)

Tight junctions in epithelia with high transepithelial transport have

very high permeability.

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PROXIMAL TUBULE
Reabsorbs 67% of filtered water, Na+, Cl-, K+ and other solutes
Due to the presence of the brush border ( surface area) and
abundance of mitochondria ( energy)
Key element in reabsorption: Na+,K+-ATPase in the basolateral
membrane

SODIUM REABSORPTION

FIRST HALF OF THE PROXIMAL TUBULE

Na+ is reabsorbed with bicarbonate (HCO3-) and a number of other

solutes (e.g. glucose, amino acids, Pi, lactate)
Mechanisms:
(1) Na-H antiporter

Found in the apical membrane

Na+ reabsorbed, H+ excreted

CO2 + H20 combines to form carbonic acid(H2CO3) acted upon by

carbonic anhydrase splits up into H+ and HCO3- H+ goes to
tubular fluid, HCO3- to the circulation

Na+ goes to the circulation via Na+,K+-ATPase

Absorbed: Na+ and HCO3-

Excreted: H+

3.01a

(2) Na-glucose symporter

Na+ is coupled with glucose in the apical membrane

Na+ goes to the circulation via Na+,K+-ATPase
Glucose goes to the circulation via passive transport mechanism
(GLUT2)
Reabsorption of many organic molecules is so avid that they are
almost completely removed from the tubular fluid in the first half of
the proximal tubule.
Absorbed: Na+ and glucose

SECOND HALF OF THE PROXIMAL TUBULE

Na+ is reabsorbed with Cl- via transcellular and paracellular

pathways


















Mechanisms:
(1) Transcellular pathway

2/3 of NaCl is reabsorbed through this process

Na-H antiporter and one or more Cl-anion antiporter

H+ secreted by Na-H antiporter combines with the anion secreted by

Cl-anion antiporter and reenters the cell

Na+ goes to the circulation via Na+,K+-ATPase

Cl- goes to the circulation via a K+-Cl- symporter in the basolateral

membrane

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Renal Physiology I

(2) Paracellular Pathway

1/3 of NaCl is reabsorbed through this process

Happens because of the rise of [Cl-] in the tubular fluid that creates a
[Cl-] gradient

Happens stimultaneously with the transcellular pathway

Movement is isosmotic (equal movement of Na and water)

SOLUTE CONCENTRATION IN TUBULAR FLUID AS A FUNCTION OF
LENGTH ALONG THE PROXIMAL TUBULE

In the first half of the proximal tubule, certain substances have

already been absorbed completely such as amino acids, glucose and
bicarbonate.
Farther down the proximal tubule, there is still active reabsorption
of Na+ and Cl-.
Certain substances are easily reabsorbed compared to others

3.01a

WATER REABSORPTION
Driving force: transtubular osmotic gradient established by solute
reabsorption
Apical and basolateral membranes of proximal tubular cells express
aquaporin water channels.
SOLVENT DRAG: important consequence of osmotic water flow "
some solutes, especially K+ and Ca++, are entrained in the reabsorbed
fluid and reabsorbed by the process of solvent drag
Na and other solute reabsorption into the lateral intercellular space
(through apical membrane)

Fluid osmolality of the tubular fluid
Fluid osmolality of the lateral intercellular space (in relation to the
tubular fluid)

Water flows by osmosis across the tight junctions and proximal tubule
cells (to the intercellular space)

hydrostatic pressure in the lateral intercellular space

Fluids move into the capillaries

Water is reabsorbed

REMEMBER! Proximal tubule reabsorption is ISOSMOTIC " osmolarity
does not change
How will osmolality decrease?

Tubules should exhibit impermeability to water, as in the
case of the thick ascending limb, early distal tubule, late distal tubule
(unless acted upon by ADH) and collecting duct (unless acted upon by
ADH).




















PROTEIN REABSORPTION

Protein: almost 100% reabsorption

Urinalysis: should be negative for protein

Enzyme is easily saturated

o
protein diet saturates enzyme proteinuria - protein is
found in urine (normal)
o
Disruption of glomerular filtration to protein filtered
protein proteinuria

Partial enzyme degradation of protein in the surface of proximal tubule
cells

Endocytosis

Further intracellular breakdown of proteins into amino acids

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Renal Physiology I

Amino acid leaves the cell via the basolateral membrane

Enters capillary circulation

ORGANIC CATION AND ANION SECRETION

End products of metabolisms and exogenous organic compounds,

including numerous drugs and toxic chemicals, circulating in plasma
o
Many are not readily filtered so they are secreted from the
peritubular capillaries.

1. Organic Anion Secretion: p-aminohippuric transport

Basolateral membrane: elimination from the circulation in exchange

of an alpha-ketoglutarate

Apical membrane: secreted to tubular fluid in exchange of an anion

PAH enters the cell via the basolateral membrane in exchange for KG
(antiport) coming from the metabolism of glutamate in the cell

KG then reenters the cell in symport with Na+

KG recycles in the basolateral membrane

PAH drives the movement towards the apical membrane

PAH moves toward via the PAH-Anion antiporter

PAH in the TF

2. Organic Cation Secretion

Organic cation is secreted in exchange of one H+

One mechanism by which H+ is brought back into the cell (recall that
H+ is secreted via the Na-H antiport)

3.01a

Renal Physiology I

LOOP OF HENLE

Important in the concentration and dilution of urine

Important in the countercurrent mechanism
Reabsorbs approx. 25% of filtered Na+ and K+
Key element in reabsorption: Na+-K+ ATPase osmolarity of
medullary interstitium in the thick ascending limb
NaCl reabsorption: only in thin ascending and thick ascending limbs
H2O reabsorption: only in descending thin limb
Thick ascending limb:
o
1Na+-1K+-2Cl- symporter: (in the apical membrane) mediates
Na+ movement across the cell
o
Na-H exchanger
o
Tight junctions: Na+, K+, Ca++, Mg++ (but not H2O " decreases
the osmolarity of the tubular fluid)
o
diluting segment increased reabsorption

Mechanisms:

(1) Transcellular Pathway

1Na+-1K+-2Cl- symporter

Intracellular Na+ (via Na+,K+-ATPase) < TF

Na+ moves together with K+ and 2 Cl- across the apical membrane (AM)
via 1Na+-1K+-2Cl- symporter
(downhill movement of Na+ and Cl- releases potential energy
which drives K+ uphill inside the cell)

Na+ leaves the cell at BLM via Na+,K+-ATPase

K+ and Cl- leave the cell by separate pathways

Na-H Antiporter

Na entry to the apical membrane is coupled with pumping out of H+ via
Na-H antiporter

H+ secretion results in NaHCO3 reabsorption
(explained earlier as to why)

Na+ leaves the cell at BLM via Na+,K+-ATPase

HCO3- leaves the cell by diffusion

(2) Paracellullar Pathway

Voltage across the thick ascending limb is important in the

reabsorption of several cations such as Na+, K+, Ca2+ and
Mg2+ via the paracellular pathway.

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salt transport positive charge of the lumen

TF is positively charged compared to blood

Na+, K+, Ca2+ and Mg2+ in the TF will move to the more negative side
(blood) via electrical gradient at the tight junctions

osmolality of TF to 150mOsm/kgH2O
(water is not reabsorbed at the thick ascending limb)

DISTAL TUBULE AND THE COLLECTING DUCT
Reabsorbs approximately 7% of filtered NaCl
Water reabsorption depend on ADH levels
Na+, Cl- and Ca2+ reabsorbed in the early segments
Impermeable to water

LATE DISTAL TUBULES AND COLLECTING DUCT:
Cell Types:
1.
Principal Cells reabsorb Na+ and water and secrete K+; Na+,K+ATPase
2.
Intercalated Cells secrete H+ or HCO3- and regulate acid-base
balance; ATP-driven H+ pump

3.01a

Renal Physiology I

SUMMARY
NACL TRANSPORT ALONG THE NEPHRON
Percentage
Mechanism of Na+ transport
Filtered
across the AM
Reabsorbed
Proximal tubule
67%
Na+H+ exchange
Na+-contransport with
glucose, amino acids and
other organic solutes
Na+H+Cl-Anion exchange
Loop of Henle
25%
1Na+1K+2Cl- symport
Early Distal
~4%
NaCl symport
Tubule
Late DT and
~3%
Na+ channels
Collecting Duct


WATER REABSORPTION ALONG THE NEPHRON
Segment
Percentage
Mechanism of water
Filtered
absorption
Reabsorbed
Proximal tubule
67%
Passive
Loop of Henle
15%
DTL only, passive
Early Distal
0%
No water reabsorption
Tubule
Late DT and
~8-17%
Passive.
Collecting Duct
ADH must be present.


Segment

Transers Message

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