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RENAL PHYSIOLOGY (CHEAH SOOK PENG, CANDACE) (PART 2: SOLUTE REABSORPTION,…
RENAL PHYSIOLOGY
(CHEAH SOOK PENG, CANDACE)
PART 1: GLOMERULAR FILTRATION
1. Introduction to the physiology of the kidney.
a)
Kidney
: many roles- maintain homeostasis of body
receive 25% of
cardiac output
filter
blood, excrete metabolic waste
retrieve
filtered substances needed by the body: water, glucose, electrolytes, & low–molecular-weight proteins
respond to changes
by altering rate of re-absorption/ secretion of water, electrolytes, acid-base substances
produce
hormone
: regulate blood pressure & RBC production
b) works by many cell types, each with specific responses to direct/indirect signals, forming the
NEPHRON
(comprises of:)
glomerulus
: filters blood
Renal tubule Segments
:
absorb filtered substances
secrete plasma components into tubule fluid
Renal Cortex
:
nephrons merge into
collecting duct system
(traverses kidney)
empties into
renal pelvis
2. The glomerulus filters the blood.
compact network of capillaries
retains cellular components & medium-high mol. weight proteins within the vessels
extruding fluid identical to plasma called
glomerular filtrate
Rate of Glomerular Filtration (GFR): mL/min/kg
example
: avg. size beagle: 10kg with (w/) GFR of 3.7 mL/min/kg
approx. 37mL of glomerulus filtrate/min
53.3 L of glomerulus filtrate / day (~27x beagle's ECV)
3. Structure of the glomerulus - efficient, selective filtration
Glomerular Tuft
network of capillaries
renal arterial blood flows to afferent arteriole
divide to glomerular capillaries
capillaries combine form efferent arteriole
moves filtered blood away from glomerulus
encased by
Bowman's capsule
- parietal epithelium (single layer of cells)
Bowman's space
: glomerular filtrate 1st appears
filtrate enters lumen of 1st segment of
proximal tubule
Glomerular capillaries
Structure
- determine rate & selectivity of glomerular filtration (GF)
divided to
3 layers
a) capillary endothelium
single layer of thin cells- faces the blood in capillary lumen
Endothelial fenestrae- transcellular pores that conduct water & noncellular components in the blood to GBM
b) Glomerular basement membrane (GBM)
acellular, various glycoproteins (laminins, type IV collagens, nidogens), agrin (mature), prelecan (dev. glomeruli)
GBM- thicker & contains glycoprotein
isoforms
3 layers (fusion of basement membranes of endothelial and epithelial cell layers
Lamina densa (dense layer)
dark, resistant to passage of electrons, tightly packed glycoprotein fibrils
Lamina rara interna (inside thin layer)
endothelial side of GBM, loose network of glycoprotein fibrils
Lamina rara externa (outside thin layer)
epithelial side of GBM, loose network of glycoprotein fibrils
c) visceral epithelium
Podocytes-
layer of intricate, interlocking cells
Primary & secondary foot processes
- long, narrow extensions
interdigitate w/ foot processes of other podocytes
wrap around individual capillaries
Epithelial Slit Diaphragm
spans btwn adjacent foot processes
nephrin (transmembrane protein) - critical component, extending from adjacent foot processes interacts to form slit diaphragm
4. Glomerular filtration rate (GFR)
determined by:-
mean net filtration pressure
permeability of the filtration barrier
surface area available for filtration.
GLOMERULAR CAPILLARY WALL
makes barrier to forces favor/oppose blood filtration
Favouring Filtration
movement of H2O & solutes acress glomerular capillary wall
hydrostatic pressure of blood in capillary & oncotic pressure of fluid in Bowman space (
ultrafiltrate
)
Usually
oncotic pressure
of ultrafiltrate is insignificant cz medium- to high- mol. proteins NOT filtered
main driving force for filtration:
glomerular capillary hydrostatic pressure
Opposing Filtration
plasma oncotic pressure within glomerular capillary & hydrostatic pressure in Bowman's space
Net Filtration Pressure
(NFP)
diff btwn
capillary hydrostatic pressure
(favoring filtration) &
capillary oncotic pressure
&
hydrostatic pressure of ultrafiltrate
(opposing filtration)
Relationship:
Pf = Pgc − (πb + Pt )
Blood travels thru glomerular capillary
fluid component of plasma forced
across capillary wall
Plasma protein
retained in capillary lumen
Plasma oncotic pressure ↑ along capillary bed
↓ plasma vol. along capillary bed cause ↓ in hydrostatic pressure in capillary
-change is small: resistance of efferent arteriole
NFP ↓ along capillary bed
BUT when blood flow ↑ through glomerular capillaries, ↑ in capillary oncotic pressure blunted
↑ filtration in distal portions of glomerular capillaries
GFR = mean net filtration pressure + permeability of filtration barrier + surface area available for filtration
Permeability of Filtration Barrier
- structural & chemical characteristics of glomerular capillary wall
product of this + its surface area = ultrafiltration coefficient (Kf)
5. Filtration Barrier Is Selectively Permeable
(permselectivity)
Permselectivity of filtration barrier
: responsible for diff in rate of filtration of blood components
Only water and solutes are freely filtered and not retained in bloodstream
radius of 2nm or less filtered w/out restriction
Another Factor: Net Eelectrical charge of a molecule
free filtered: Cationic form > neutral form > anionic form
of the same molecule
Reason
:
charge-selective barrier
in the glomerular capillary wall that is created by
negatively charged residues of glycoproteins
incorporated in the glomerular basement membrane
fixed negative charges
repel
negatively charged plasma proteins
inhibit their passage across the filtration barrier.
Another Factor: shape and deformability of the molecule
6. Glomerular Filtration Rate (GFR) is regulated by systemic and intrinsic factors.
kept within
physiological range
by
renal modulation of systemic blood pressure
&
intravascular vol.
&
intrinsic control of renal blood flow, glomerular capillary pressure & ultrafiltration coefficient (Kf)
Renal effects on
systemic
BP & vol. mediated thru
renin-angiotensin-aldosterone
system
(RAAS)
RAAS imp. reg. of GFR & renal blood flow
Renin (hormone)
produced @ wall of afferent arteriole
by
granular extraglomerular mesangial cells
(specialized juxtaglomerular cells)
Release stimulated by ↓ in renal perfusion pressure
catalyzes the transformation of
angiotensinogen
, which is produced by the
liver
,
to angiotensin I.
Angiotensin I
→ active
angiotensin II
by angiotensin converting enzyme (ACE) @ vascular endothelium of lung / kidney- interstitial cap. endothelium & proximal tubule
angiotensin I → angiotensin II @ kidney
regulate renal blood flow & transport processes
independent of systemic effects.
*Angiotensin II
vasoconstrictor- ↑ systemic BP & renal perfusion pressure
activates Na uptake in:-
proximal tubule
distal convoluted tubule
collecting duct
stimulates the release of
aldosterone
from the adrenal gland
Release
sopressin
from pituitary
enhance water reabsorption
↑ Na and H2O retention, intravascular vol. & vascular resistance
↑ angiotensin II, suppression of renin released
negative feedback: renal perfusion & GFR
INTRINSIC FACTORS
Intrinsic control
- mediated by 2 auto-regulatory sys.
control resistance to flow in afferent & efferent arterioles
tubuloglomerular feedback
(TGF)
auto-reg. mechanism: changes in
tubule fluid delivery
associated with
juxtaglomerular apparatus
↑ glomerular filtration, ↑ tubule fluid flow & NaCl conc. in tubule fluid @ macula densa
↑ NaCl in NKCC2 @ macula densa → depolarisation of cells & basolateral
release of ATP
ATP release suppress renin release @ juxtaglomerular xells, ↑ resistance @ afferent arteriole, ↓ glomerular capillary perfusion pressure, triggers mesangial cell contraction, & ↓ Kf
lead to ↓ GFR @ single-nephron GFR → prevents excessive loss of fluid & solute
↑ NaCl delivery to distal nephron stimulates production of vasodilatory agents by macula densa cells
blunts TGF response (brake to prevent excessive ↓ in single-nephron GFR)
myogenic reflex
afferent arteriolar constriction, ↑ arteriolar wall tension
↑ resistance to blood flow when ↑ perfusion pressure
Vasoconstrictive arm =
depolarisation
of vascular SM cells in pre-glomerular arteries & arterioles
rapid entry of calcium thru VG calcium channels= stimulate SM cell contraction
response is independent of renal innervation, influenced by chemical mediators (Nitric Oxide)
auto-regulated mechanism
changes in glomerular perfusion
Endothelium produce vasoconstrictors & vasodilators
Endothelium-derived constricting factors
thromboxane A2 (mediates PGE2 (a metabolite of arachidonic acid)
endothelin
angiotensin II
Endothelium-derived relaxing factors
Nitric oxide (NO)
produced in the kidney by oxidation of l-arginine
prevents renal damage by quenching reactive oxygen species,
prostacyclin (prostaglandin I2)
PGE2
intrarenal regulation of vascular tone and glomerular filtration is subject to complex interactions among the various regulatory mechanisms
SYSTEMIC FACTORS
many hormones reg. blood vol. (BV)
Enhance water & solute reabsorption by kidney & ↑ BV
Atrial natriuretic peptides,
produced in the cardiac atria, cause both natriuresis (sodium wasting) & diuresis (water wasting) & ↓ BV
also affect systemic blood pressure, renal perfusion, and ultrafiltration
vasoconstrictors can affect the other determinant of GFR, the ultrafiltration coefficient Kf. (cause mesangial cells to contract, ↓ filtration area)
Factors ↑ GFR: insulin-like growth factor & high dietary protein
↑ GFR from high-protein diets: cause more rapid progression of glomerular injury & renal failure
7. GFR Is Measured by Determining the Plasma Clearance Rate of a Substance
The
rate of clearance
is measured by the rate of elimination of a substance ÷ its plasma conc.
net clearance rate of a substance
is the sum of the rates of filtration and secretion minus the rate of reabsorption of the substance.
INULIN
freely filtered by the glomerulus but is neither reabsorbed nor secreted by the renal tubule cells.
rate of its disappearance from the blood after intravascular injection is strictly related to the rate of glomerular filtration.
CREATINE
most widely used measure of glomerular filtration
byproduct of muscle metabolism that is handled similar to inulin by the kidney
freely filtered, is not reabsorbed by the tubule,
serum creatinine level
freq. used to assess renal function.
very small increase in serum creatinine correlates with
a large reduction in glomerular filtration rate
GFR is better expressed on the basis of
body weight or body surface area
—that is,
as milliliters per minute per kilogram or milliliters per minute per square meter
— because of the
large variation in size within individual species.
PART 2: SOLUTE REABSORPTION
1. The renal tubule reabsorbs filtered substances.
Importance
-example: 10kg beagle, 53.3L GF per day
ultrafiltrate contains the same conc. of salts & glucose as plasma
without tubular reabsorption
urinary loss of
sodium
chloride
potassium
bicarbonate
glucose
alone would total more than 500 g of solute.
renal tubule efficiently retrieves these and
other constituents of the ultrafiltrate
100% of filtered glucose reabsorbed by the proximal tubule; approx. 99% of the filtered water & sodium are retrieved.
2. Renal tubule function may be assessed by determining
fractional excretion rate.
Fractional Excretion Rate
: net rate of tubular reabsorption and secretion of a filtered substance
more practical in clinical situations to use
creatinine
as the
reference substance
fractional excretion rate (typically of sodium) used to assess the f
unctional integrity of the renal tubules
in clinical cases of
acute renal failure
3. The proximal tubule reabsorbs the bulk of filtered solutes.
rate of reabsorption and secretion of filtered substances varies among segments of the renal tubule.
proximal tubule reabsorbs more ultrafiltrate than other tubule segments combined (60%)
movement of tubule fluid into blood thru:
transcellular pathway
subs. cross apical plasma membrane, cytoplasm & basolateral plasma membrane (into interstitial fluid)
occurs by carrier-mediated transport
factor: vast plasma membrane surface area of prox. tubule
basolateral surface area = apical surface area in portions of the proximal tubule
Benefit: ↑ capacity for solute transporters & ↑ exposure to luminal & interstitial fluids.
paracellular pathway
subs. pass thru across
zonula occludens
(cell junction)
subs. enter lateral intercellular space
reabsorbed subs. can be taken up by the
peritubular capillary
.
Transport occurs by
passive diffusion
/
solvent drag
peritubular capillary
origin: glomerular efferent arteriole, subdivides, and wraps closely around the basal aspect of the proximal tubule
has low resistance
high peritubular plasma oncotic pressure/low peritubular capillary hydrostatic pressure:
favor fluid & solute uptake
from the interstitium into the bloodstream.
Reabsorption of solutes
by active transport of Na ions by s
odium-potassium-adenosinetriphosphatase (Na+,K+-ATPase) pump
@ basolateral plasma membrane
↓ intracellular Na ions conc., ↑ intracellular K ions conc.
Bicarbonate (HCO3-) reabsorption
Secreted H ions + filtered HCO3- in tubule fluid = Water and CO2 (catalyst: carbonic anhydrase)
Carbonic anhydrase catalyses
hydroxylation
of CO2 w/ OH- from water, form H+ & HCO3-
Prox. tubule reabsorbs 60% - 85% of filtered HCO3-
Chloride ion (Cl-) reabsorption
occurs through
paracellular
&
transcellular
routes.
As solutes (ions of sodium, bicarbonate, glucose, etc) are selectively reabsorbed & water is taken up along with these solutes,
↑ conc. of Cl− in the tubule fluid, forming chemical gradient for Cl− movement toward the blood side
Early prox. tubule: uptake of Na+ > anions (net +ve charge): favor anion re-absorption
zonula occludens
highly permeable to Cl−
passive,
paracellular
transfer of Cl− from the tubule lumen to the interstitial fluid
Trancellular
Cl- reabsorption also @ prox. tubule
Distal portion of prox. tubule: Na+ uptake occur by electrically neutral NaCl uptake
facilitated
by coordinated Na+ and Cl−-coupled transporters & by passive reabsorption of Na+ through the paracellular pathway.
As Cl- move down chemical gradient, carries Na+ thru electrostatic attraction
Calcium ions reabsorption
65% filtered Ca ions reabsorbed by prox. tubule
90% of Ca ion uptake is
paracellular
Potassium ion reabsorption
passive mechanisms: paracellular
Filtered Peptides
degraded to amino acids by peptidases in the proximal tubule brush border
reabsorbed by co-transport w/ Na+ across apical plasma membrane
short chain peptides: transported thru co-trans. w/ H+ by PEPT1 & PEPT2
dipeptides & tripeptides- degraded by intracellular peptidases (some exit intact to blood side)
Low-molecular-weight proteins
insulin, glucagon, parathyroid hormone, & etc. - taken up by
receptor-mediated endocytosis
delivered by endocytic vesicles to lysosomes, receptors recycled to apical plasma membrane
Proteolytic enzymes
degrade the reabsorbed proteins
Amino acids (end products), transported into interstitial fluid & returned to blood
4. The proximal tubule secretes organic ions.
endogenous
waste products and
exogenous
drugs or toxins
protein bound in the plasma and thus are poorly filtered by the glomerulus.
prox tubule clears
the subs. by
basolateral uptake
&
apical secretion
into the tubule fluid by
carrier-mediated processes
Transporters involved:
organic anion transporters
organic cation transporters
apical P-glycoprotein (Pgp)
basolateral Na+ -dicarboxylate co-transporter
several multi drug resistance transporters (MRP)
Endogenous organic compounds secreted
bile salts, oxalate, urate, creatinine, prostaglandins, epinephrine, and hippurates
Drugs and toxins secreted
antibiotics (e.g., penicillin G, trimethoprim), diuretics (e.g., chlorothiazide, furosemide), antiviral agents (e.g., acyclovir, ganciclovir), the analgesic morphine and many of its derivatives, the potent herbicide paraquat, & etc
Tubule secretion of endogenous organic ions, drugs, and toxins provides
the basis for urine testing for hormones and foreign substances
as a
reflection
of blood lvls that may be only brefly elevated
Competitive inhibitors of organic ion secretion ↑ blood lvls & prolong activity of other drugs (administered simultaneously that are excreted by this route) which
can create unintended drug toxicities or can be used for therapeutic advantage
Tubule secretion plays a larger role in birds than in mammals
End product of protein metabolism is
uric acid.
5. The thick ascending limb (TAL) & distal convoluted tubule (DCT)
reabsorb
salts &
dilute
the tubule fluid.
structure of the tubule epithelium changes abruptly @ end of prox. tubule
downstream from the straight portion of prox. tubule: thin limb of Henle’s loop
active transport of solutes in this segment is virtually nonexistent
Fx: determined by the segmental distribution of specific solute & water transporters & passive permeability properties & its spatial orientation in the medulla
Urine conc. mechanism
TAL
: many mitochondria & basolaterl plasma membrane infoldings
high capacity for active solute transport
electrochemical gradient for Na+ drives ion uptake thru NKCC2 co-transporter
Cl- absorption and K+ secretion cause lumen-positive voltage relative to the interstitium.
lumen-to blood electrical gradient drives diffusion of the cations, Ca2+ & Mg2+
through cation-selective paracellular channels
formed by tight junc. proteins-
claudin
apical co-trans. in TAL inhibited by
loop
diuretics like bumetanide & furosemide
DCT
: taller epithelium and a dense array of mitochondria
contains apical NaCl co-trans. (NCC) that mediates Na+ movement from tubule fluid down the chemical gradient for Na+
Cl− exits through basolateral ClC-K/barttin Cl− channels, driven by the electrical gradient.
apical NaCl co-transporter is inhibited by
thiazide
diuretics.
connecting segment
: has heterogeneous cell population that connects the nephrons to the collecting duct system.
TAL and DCT reabsorb sodium, chloride, calcium and magnesium ions
they do it against a high gradient
when fluid leaves DCT: 90% of filtered salts are reabsorbed (osmolality of fluid is reduced)
salt reabsorption in the TAL and DCT is driven by Na+,K+-ATPase in basolateral plasma membrane
TAL and DCT: impermeable to water
avid reabsorption of salts w/out water cause hypotonic tubule fluid (diluting segments)
Dilution of the tubule fluid takes place regardless of the volume status of the animal
prevents water overload and plasma hypotonicity, & also generates a hypertonic medullary interstitium
6. The collecting duct (CD)
reabsorbs NaCl & can
secrete
or
reabsorb
potassium.
begins with the connecting segment, which follows the DCT
connecting segment contains several distinct epithelial cell types
connecting segment cells
intercalated cells
has many intracytoplasmic vesicles and mitochondria
account for the remainder of the cortical and outer medullary collecting duct cells
subpopulation of intercalated cells contributes to Cl− reabsorption via an apical Cl−
/HCO3- exchanger
pendrin
& basolateral Cl− channels.
pendrin
activity enhances ENaC activity in principal cells
DCT cells
principal cells
has fewer intracytoplasmic vesicles and mitochondria but more extensive basolateral plasma membrane infoldings
major cell type in the initial collecting duct, the cortical collecting duct, and the outer medullary CD (2/3 of cells in most regions)
NaCl reabsorption in the CD is the primarily fx
Control of net renal K+ excretion (fx of CD)
occurs for 2 reasons
the apical K+ channel, ROMK, more permeable than basolateral K+ channel
lumen-negative electrical potential favors K+ secretion
another fx of CD: reabsorb K+
intracellular K is actively transported in exchange for hydrogen ions in the tubule fluid by apical H+,K+-ATPase
7. Solute transport is regulated by
systemic
and
intrarenal
signals.
rate of reabsorption of sodium, chloride, phosphate, and other solutes is regulated by specific hormones.
distal tubule & CD control the ultimate rate of excretion of electrolytes & water to maintain homeostasis
controlled by several hormones, including angiotensin II, aldosterone, antidiuretic hormone, endothelin-1, atrial natriuretic peptide, parathyroid hormone, 1α,25-(OH)2–vitamin D3, & calcitonin
8.
Angiotensin II
stimulates Na uptake in
proximal tubule
distal nephron
collecting duct.
These segments contain specific angiotensin II receptors (AT1
receptors) that, when activated, increase Na+ transport.
In contrast, activation of angiotensin type 2 receptors (AT2) enhances renal Na excretion
9.
Aldosterone
enhances Na reabsorption & K secretion.
aldosterone: mineralocorticoid hormone that is secreted by the
adrenal cortex.
release is stimulated by systemic hypotension through the renin-angiotensin system.
acts on connecting segment cells & principle cells of CD to enhance Na+ reabsorption (enhances H2O reabsorption ↑ fluid vol.)
stimulates Na+,K+-ATPase activity & ↑
open probability
of apical plasma membrane Na+ channels (ENaC)
also stimulated by
hyperkalemia
(elevated plasma K+ lvl) - important role in reg. K+ homeostasis
Aldosterone indirectly/directly ↑ activity of apical K+ channel, ROMK
10. Other hormones & ligands that regulate Na transport:
antidiuretic hormone (ADH),
nitric oxide(NO)
endothelin-1
atrial natriuretic peptide (ANP)
ADH
released when an animal is
volume depleted
,
dehydrated
, or
hypotensive
(enhances salt reabsorption from the TAL & CD)
results from vasopressin-stimulated increases in the activity of the apical Na+,K+,2Cl− co-transporter (NKCC2) in TAL & ENaC in CD
allows maximal salt & water conservation: the ↑ salt uptake contributes to the interstitial osmolarity & enables enhanced water reabsorption in the CD
NO
type of gas produced by the catabolism of L-arginine, catalyzed by NO synthase (NOS) in renal endo/epithelial cells
Inhibit Na+ uptake mechanisms in
several renal tubule segments
important role in reg. systemic extracellular fluid volume & BP
ENDOTHELIN-1
a peptide hormone produced in the kidney in
CD, endothelial cells, and the TAL of Henle’s loop.
↑ renal NaCl & water excretion by effects on epithelial transport and renal microcirculation, mediated by NO & prostaglandins.
ATRIAL NATRIURETIC PEPTIDE (ANP)
produced in the cardiac
atria.
Stimulated by
atrial distention
in healthy subjects
plasma ANP levels are ↑ in patients with congestive heart failure & other conditions causing extracellular fluid retention.
inhibits aldosterone and renin release & increases renal Na+ excretion
11. Phosphate uptake in the proximal tubule is
decreased by parathyroid hormone (PTH).
Filtered phosphate is reabsorbed via Na-coupled phosphate transporters (NaPi2a, NaPi2c, PiT2) located in the proximal tubule brush border;
mediated largely by changes in the apical abundance of these transporters.
PTH ↓ brush border NaPi2a, NaPi2c, and PiT2, thereby ↓ phosphate uptake & ↑ urinary phosphate excretion
12. Ca reabsorption in the distal nephron & connecting segment is
enhanced by parathyroid hormone, vitamin D3, & calcitonin
.
65% filtered Ca2+ absorbed in prox. tubule, majority of Ca2+ reabsorption in prox. tubule is
paracellular & passive
20% of filtered Ca2+ is reabsorbed in TAL of Henle's loop- passive, paracellular means
small % of Ca2+ reabsorption in TAL occurs by
transcellular transport
DCT & connecting seg. reabsorb additional 10% of filtered Ca2+ by active transcellular transport
1-2% Ca2+ reabsorbed in CD
Hypocalcemia (low plasma Ca2+ lvl): stimulates PTH release- affect bones, intestines, kidneys to raise plasma Ca2+ lvl.
Hormone vit. D converted to active form in prox. convoluted tubules stimulated by PTH.
vit. D3 located @ DCT and connecting segment: ↑ cellular content of Ca2+-binding protein (calbindin 28k) and enhance Ca2+ reabsorption
Calcitonin
: ↓ serum Ca2+ conc & ↓ renal Ca2+ excretion by enhancing Ca2+ reabsorption in TAL and DCT
PART 3: WATER BALANCE
1. The kidney maintains water balance.
animals must constantly guard against
desiccation
(removal of moisture), thus their kidneys evolved to
reabsorb most of the water in the glomerular filtrate
.
Eg: normal conditions, a 10kg beagle that produces 53.3L of glomerular filtrate per day may
reabsorb more than 99% of the water contained in the glomerular filtrate
,
excreting only 0.2 to 0.25 L of urine
water-deprived dog
with normal renal function can produce urine that is 7-8 times more
concentrated
than the osmolality of plasma
kidney also can produce
hypotonic urine
in response to a
water overload
same dog can excrete urine with an osmolality as low as 1/3 that of plasma
2. The proximal tubule reabsorbs more than
60% of filtered water.
prox. tubule reabsorbs the majority of the glomerular filtrate.
takes up solutes from the tubule fluid by both
active
and
passive
means.
Removal of solute from the tubule fluid creates a slight gradient
favoring the movement of water
into
the
cells
and the
intercellular
spaces
complex apical brush border & basolateral plasma membrane infoldings create large surface areas- highly
permeable
to water due to water channel, aquaporin-1 (
AQP1
), in the apical & basolateral plasma membranes throughout the prox. tubule.
result in rapid movement of water from the tubule fluid to the interstitial fluid.
high oncotic pressure & low hydrostatic pressure in peritubular capillaries
favor the movement of reabsorbed water
&
solute
from the interstitial fluid→blood.
because water is reabsorbed nearly isotonically with salt:
osmolality of the tubule fluid
remains similar from Bowman’s space
to the beginning of the thin descending limb of Henle’s loop.
3. The kidney can produce
concentrated
or
diluted
urine.
3 main components
(B) dilution of the tubule fluid by the thick ascending limb and the distal convoluted tubule
which allows excretion of dilute urine;
C) variability in the water permeability of CD in response to ADH
determines the final urine concentration.
A) generation of a hypertonic medullary interstitium
allows excretion of concentrated urine;
all factors are necessary for urine conc. & dilution- operative at any given time
kidney can respond immediately to changes in ADH levels w/ changes in urine osmolality & water excretion.
4. A
hypertonic medullary interstitium
is needed to form conc. urine
animals usually produce urine that is conc. well
above plasma osmolality
Excretion of conc. wastes conserves water & ↓ the vol. of water that is consumed to
prevent dehydration
Factor A and C (prev mentioned in 3.) are responsible for formation of conc. urine
hypertonicity of the medullary interstitium
is produced
& maintained by:
a) the reabsorption of osmotically active substances by tubules in the medulla
b) he removal of water from the medullary interstitium by the vasa recta
5. Short-loop & long-loop nephrons have diff roles in urine conc.
pg. 502, 5th ed.
nephrons of mammal kidney- subdivided into
superficial
&
juxtamedullary
nephrons
based on the location of their respective glomeruli
superficial nephrons
short loops of Henle
that extend only into the inner stripe of the outer medulla
short-loop nephrons
have a descending thin limb that parallels the TAL
do not have an ascending thin limb
; the thin descending limb merges w/ thick ascending limb
near the hairpin turn
Juxtamedullary nephrons
long loops of Henle
that extend
deep into the
inner medulla.
long-loop nephrons
have several segments of descending & ascending thin limbs with specific urea & water transporter expression
Role: maintaining the medullary hypertonicity & urine conc. ability
responsible for the kidney’s ability to concentrate urine at a much ↑ lvl than osmolality of plasma.
6. NaCl reabsorption by the medullary TAL generates medullary hypertonicity.
TAL of Henle’s loop actively reabsorbs NaCl; impermeable to water
↑ the osmolality of the interstitial fluid- generating medullary interstitial hypertonicity & a lumen-to-interstitium osmotic gradient.
allows water to be abstracted from water-permeable descending thin limbs & returned to the circulation
occurs in both
shortloop
and
long-loop
nephrons.
7. Urea reabsorption by the inner medullary CD (IMCD) & urea recycling
enhance medullary hypertonicity
.
The inner medullary collecting duct (IMCD) also actively reabsorbs NaCl
Role of more important contribution is to the medullary hypertonicity is the reabsorption of urea
terminal IMCD is
highly permeable to urea
via specific urea transporters (UT-A1, UT-A3)
urea remains in the tubule fluid until it reaches the terminal IMCD deep in the medulla.
urea reabsorption by the IMCD is enhanced by ADH
conditions demand water conservation & ADH is released, urea reabsorption is enhanced & the osmotic gradient for water uptake
↑
.
thin limbs of Henle’s loop permeable to urea, the high interstitial urea conc. drives urea
into the thin limb luminal fluid
.
urea reabsorbed from the terminal IMCD & taken up by the thin limbs → recycled back to the IMCD
Mammals-
urea recycling
enhances the efficiency of the urine-concentrating mechanism.
birds
: urea is nearly absent in the medullary interstitium;
urates
do not contribute appreciably to osmotic pressure because they have low water solubility
medullary hypertonicity in birds appears to depend on single-solute (NaCl) recycling.
8. The
countercurrent
mechanism ↑ medullary interstitial osmolality w/ minimal energy expenditure.
Countercurrent mechanism
: responsible for the progressive amplification of the medullary hypertonicity initiated by the active reabsorption of salt by the thick ascending limb of Henle’s loop
2 characteristics:
a) anatomical arrangement of the thin limbs of Henle’s loop
b) differential water & salt permeabilities of the descending and ascending thin limbs
thin limbs of Henle’s loop
in
juxtamedullary
nephrons
extend deep into the
inner medulla
descending & ascending thin limbs joined by a sharp,
hairpin turn
hairpin turns slow the rate of blood flow, which helps maintain the osmotic gradient required for water reabsorption.
The limbs are parallel & juxtaposed, with the tubule fluid flow in opposite directions
descending thin limb
comes from
straight portion
of the prox tubule
& runs parallel to thick ascending limb of Henle’s loop
long-loop nephrons
contains AQP1 water channels and is highly permeable to water.
Descending thin limb @ outer medulla- not permeable to salt
osmolality
of the
medullary interstitial fluid
: progressively ↑ in the
deeper regions of the medulla
tubule fluid osmolality ↑ until it reaches its max. conc. @ the hairpin turn.
descending thin limbs in the inner medulla are
salt permeable
thin limb ascends (↑) thru regions of ↓ interstitial osmolality, the conc. luminal fluid flows thru ↓ ambient osmolalities, & tubule fluid equilibrates w/ interstitial fluid
ascending (↑) thin limb is impermeable to water & permeable to NaCl
equilibration occurs by diffusion of NaCl from the tubule fluid → interstitial fluid
tubule fluid osmolality ↓ & solute is added to the interstitium,
RESULT
Passive means: thin limbs reabsorbed both water & salt
Water reabsorbed from the descending thin limb
salt was reabsorbed from the ascending thin limb
maintain medullary hypertonicity.
9.
Countercurrent exchange in the vasa recta
(straight arterioles of the kidney)
- removes water from the medullary interstitium w/out reducing medullary interstitial hypertonicity.
diffusion of water from the descending thin limb into the interstitium would
dilute the effect of salt
&
urea
transport into the interstitium
cause
swelling
of the inner medulla
(if it were not for the ability of the vasa recta to
remove the reabsorbed fluid
)
vasa recta
permeable to water, salts, and urea.
high plasma oncotic pressure in the vasa recta @ medulla favors movement of water into the capillary lumen
luminal NaCl & urea conc. equilibrate with the interstitial concentration.
plasma osmolality & urea conc. ↑ at the vasa recta @ hairpin turn → fall as the vessels ascend out of the medulla
Net Effect
: when ascending vasa recta leave medulla, got net movement of fluid into capillary
a) plasma oncotic pressure falls
b) blood flow in ascending vasa recta is approx. double than in descending vasa recta
10. Active NaCl reabsorption @ TAL & DCT dilutes the tubule fluid
TAL and DCT reabsorb Na+ → drive Cl- reabsorption with mechanisms described prev
(PART 2, no. 5)
active solute reabsorption causes a ↓ in the tubule fluid osmolality
tubule fluid delivered to the CD is
hypotonic
,
even in a dehydrated animal
11. ADH regulates CD water permeability to determine the final urine osmolality.
arginine vasotocin in birds
Absence of ADH
dilute urine
is formed → excess water excreted
Absence of ADH:
CD impermeable to water
tubule fluid delivered by the DCT remains
hypotonic
→ the water is retained in the CD lumen
AQP2 contained in cytoplasmic vesicles in principal cells & IMCD cells
ADH upregulates urea transporters & enhances urea reabsorption by IMCD
enabling ↑ urea contribution to the medullary tonicity
DEHYDRATION / HYPOTENSION / VOL. DEPLETION
ADH released from pituitary (triggered by rise in plasma osmolarity)
rise in osmolarity due to dehydration/ salt overload / ↓ BP from systemic vasodilation, heart failure, isosmotic vol. depletion from vomiting, diarrhea, hemorrhage
animal needs to ↓ plasma osmolarity to normal / restore fluid vol. or BP
ADH PRESENT
water flows from dilute tubule fluid → cell
and then the
interstitium
↓ conc. gradient: prod.
structural alterations (cell swelling & dilation of intercellular spaces)
the now water-permeable CD traverses (cross) the inner medulla thru regions of ↑ interstitial fluid osmolality
tubule fluid equilibrates by diffusion of water into the interstitium (highly conc. urine is
eliminated
)
ADH secretion stimulates AQP2 to insert into the apical plasma membrane of these cells &
water freely passes through these channels
ADH regulates the water permeability of CD by regulating the location of the
water-channel protein aquaporin-2 (AQP2)
in CD cells
Chronic ADH stimulation
: ↑ amount of AQP2 in the CD (vice versa)
12. Cells in the Inner Medulla Adapt to Interstitial Hyperosmolality by
Accumulation of Organic Osmolytes
Cells @ inner medulla: exist in hypertonic env. & regulate cell vol. during changes in ambient osmolality
Done by accumulating organic
osmolytes
: maintain intracellular osmotic pressure & prevent cell shrinkage w/out marked ↑ in conc. of intracellular electrolytes
SUBSTANCES
(organic osmolytes)
myoinositol
amino acids
betaine
glycerophosphorylcholine (GPC)
Sorbitol
intracellular conc. of the osmolytes vary w/ diuretic state of the animal
↑ duing periods of urine conc. when medullary interstitial osmolality is maximised
↓ during diuresis, when medullary interstitial osmolality ↓
Changes in the intracellular content of organic osmolytes in response to changes in ambient osmolality occur by parallel changes in either:
the production (e.g., sorbitol, GPC) / transmembrane transport (e.g., betaine, myoinositol, amino acids) of the osmolytes
by counter-regulation of degradation of osmolytes (e.g., GPC)