Renal Physiology III Flashcards
Stimulates the secretion of adrenocorticotropic hormone (ACTH) by binding V1b
AVP
Secreted by atrial myocytes in response to increased right atrial pressure
Atrial natriuretic peptide
Exerts vasodilatory effects within afferent and efferent arterioles
ANP
ANP also decreases the sensitivity of the
TGF mechanism
Collectively, ANP increases
GFR and RBF
In general, ANP increases diuresis. To complement this activity, ANP suppresses
Renin secretion
Renal autoregulation is mediated by
Prostaglandins
If renal perfusion pressure plummets below an autoregulatory range, the mobilization of locally produced vasoconstrictors stimulates
Constriction of the afferent arteriole
Constriction of the afferent arteriole results in which three things?
- ) Decreased glomerular P
- ) Drop in GFR
- ) Reduction in post-glomerular capillary pressures
Reduction in post glomerular capillary pressures creates gradients favorable for
Reabsorption
Can lead to ischemic acute renal failure
Renal hypoperfusion
The two most common examples of renal hypoperfusion leading to ischemic acute renal failure are
- ) Prerenal azotemia
2. ) Acute tubular necrosis
An extrarenal problem causing acute renal failure due to poor renal perfusion
-an increase in plasma urea
Azotemia
Include structural changes in renal arterioles and small arteries, impaired production of vasodilatory prostaglandins, afferent arteriolar vasoconstriction, or the inability to increase efferent arteriolar resistance due to failure/pharmacologic inhibition of the RAS in a normotensive patient
Factors leading to renal hypoperfusion
Structural changes in renal arterioles and small arteries are associated with
Old age, chronic hypertension, and chronic kidney disease
The impaired production of vasodilatory prostaglandins is induced by
NSAIDs and COX-2 inhibitors
Hypercalcemia, sepsis, or the use of cyclosporine, tacrolimus, or radiocontrast agents can cause
Pathologic Afferent arteriole vasoconstriction
If you received labs that showed:
- ) Increased urinary specific gravity (greater than or equal to 1.015)
- ) Decreased Na+ and urea
- ) Elevated plasma BUN to Creatinine ratio (20:1 or higher)
than you would suspect
Renal hypoperfusion
The vast majority of filtered Na+ is reabsorbed by the
Tubule system (only 0.4% is excreted)
What are the two mechanisms by which Na+ (and everything else) can be reabsorbed?
- ) Transcellular
2. ) Paracellular
When Na+ traverses the apical and basolateral plasma membranes via transporter and/or channel activity
Transcellular reabsorption
Requires metabolic energy to establish favorable electrochemical gradients and/or to directly power Na+ transporters
Transcellular reabsorption
There is a cohort of hormonally regulated Na+ transporters and channels which enable Na+ reabsorption via transcellular reabsoption within the
Distal nephron (TAL and beyond)
Reabsorption where Na+ does not traverse the plasma membrane, but instead moves through extracellular pathways (tight junctions) between tubule epithelial cells
Paracellular reabsorption
A passive mechanism of reabsorption and thus relies on electrochemical and/or concentration gradients to drive ion movement and not metabolic energy
Paracellular reabsorption
Solvent drag,i.e. the movement of Na+ without H2O occurs via
Paracellular reabsorption
The vast majority of Na+ reabsorption (approximately 70%) occurs within the
1st half of the proximal tubule
The mechanism in the 1st half of the proximal tubule centers around basolateral
Na+/K+ ATPases
These ATPases establish a Na+ gradient that is favorable for the apical transport of Na+ from the forming urine (lumen) into the
Tubule epithelium
Movement of Na+ across the apical membrane of the proximal tubule is mediated by
Na+-glucose cotransporters (SGLT1 and 2) and Na+-H+ exchangers
Transport of Na+ from the tubule epithelial cell cytosol into the renal intersitium is accomplished by
Na+/K+ ATPases and Na+-HCO3- symporters
Hydraulic and oncotic pressures within the peritubular capillaries that surround the proximal tubule will affect
Reabsorption
Results in a low hydraulic P in the efferent arteriole and the peritubular capillaries which it supplies
Filtration from the glomerulus
This P gradient then provides a driving force for the reabsorption of H2O and Na+ from filtrate within the
Proximal tubule
As GFR changes, hydraulic and oncotic P within the efferent arteriole and peritubular capillaries will be altered and reabsorption from the proximal tubule will respnd
Accordingly
For example, at normal GFR, the peritubular capillaries possess a relatively high oncotic P and low hydraulic P, these forces favor
Reabsorption
However, as GFR increases, we see an increase in
Filtration fraction
Once again, blood entering the peritubular capillaries has a relatively high oncotic P and low hydraulic P, and
Reabsorption is favored
This relationship helps to prevent excessive
H2O and Na+ loss
Na+ is actively reabsorbed from the
Thin Ascending Limb (TnAL)
Na+ reabsorption from TAL is a vital component of the counter-current multiplier mechanism that maintains
Tonicity within the renal intersitium
Contains Na+-H+ exchangers and Na+/K+/Cl cotransporters (NKCC); each of which translocate Na+ from the lumen into the epithelium
The apical membrane of TAL cells
Important because it is the target of loop diuretics (e.g. furosemide)
NKCC
Maintains the favorable gradient that drives the NKCC symporter
Renal Outer Medullary K+ transporter (ROMK2)
Translocation of Na+ from the cytosol into the interstitium is accomplished by the
Basolateral Na+/K+ ATPase
The TAL is impermeable to
-but actively resorbs a number of ions
H2O
For this reason, the tonicity of the forming urine is relatively low in this region and this segment is referred to as the
Diluting segment
Secreted from blood into the proximal tubule transporters
Loop Diuretics
Make note that since loop diuretics are bound to plasma albumin, they can not be freely filtered through the
Glomerular capillaries
Once in the tubule, the loop diuretic uses the forming urine as the vehicle to reach and block
NKCC
With this in mind, heavy proteinuria (i.e. hyperalbuminuria) will interfere with the efficacy of a
-Not ineffective but a higher dose will be required
Loop diuretic
Suppresses Na+ reabsorption from the TAL
Loop diuretics
Since NKCC mediates K+ reabsorption concaminant with Na+, Loop diuretics promote the elimination of
NaCl, H2O, and K+
Thus loop diuretics can be referred to as
K+ wasting diuretics (also Ca2+ wasting)
Essentially all Na+ movement in the Distal Convoluted Tubule (DCT) occurs
Transcellularly
Apical Na+/Cl- cotransporters (NCC) of the DCT are blocked by
Thiazide diuretics
Local changes in lumenal potential of the DCT actually make thiazide diuretics
Ca2+ sparing
However, due to increased flow, thiazides enhance
K+ secretion in distal nephrons
The principal cells within the CCT perform a modest amount of
Na+ reabsorption
Although the absolute molar amount of Na+ reabsorption in this region appears to be
Relatively low (possibly because there is not much Na+ left in the forming urine by this point)
Is Cortical collecting tubule (CCT) Na+ reabsorption an important regulatory point?
No
Principal cells are targeted by
AVP, Aldosterone, and An-II
Since aldosterone exerts effects in this region, this is commonly referred to as the
Aldosterone-sensitive distal nephron (ADSN)
AVP stimulates the recruitment of Na+/K+ ATPases into the basolateral membrane and also activates the
Amiloride-sensitive apical Na+ channel protein ENaC
ENaC is also stimulated by
An-II
Na+ diffuses through the apical membrane of the CCT via
ENaC
The translocation of Na+ by ENaC creates a lumen-negative charge in the CCT which, in this region, favors the recretion of
K+
Hyperpolarizes the apical membrane by blocking ENaC, and in doing so disrupts the electrochemical gradient that would favor K+ secretion
-Thus is a K+ sparing diuretic
Amiloride
Also functions as a K+ sparing diuretic by blocking aldosterone bioactivity
Spirolactone
Similar to other components of the nephron, relies on basolateral Na+/K+ ATPases to establish and maintain the driving force for Na+ influx from the forming urine
Cortical Collecting Tubule (CCT)
CCT Na+ influx also depends upon membrane potential that is maintained via
ROMK2-mediated K+ secretion
A steroid hormone that is produced and secreted by cells within the adrenal cortex (Zona glomerulosa)
Alosterone
Stimulated by elevated plasma [K+]
-express AT1
Adrenal glomerulosa cells
Therefore, the secretion of aldosterone is stimulated by both
An-II and hyperkalemia
Binds to and activates the mineralcorticoid type steroid receptor within principal cells as well as a specific isoform in vascular smooth muscle
-The predominant mineralcorticoid that is produced in humans
Aldosterone
Competitive inhibitor of aldosterone binding to the mineralocorticoid receptor
-an ldosterone antagonist
Spirolactone
What effect does Aldosterone have in vascular smooth muscle?
Vasoconstriction
When you think of a steroid, think changes in
Gene transcription
The intrarenal effects of aldosterone can be divided into
- ) Acute (early, 1-4 h)
2. ) Late (chronic, greater than 4 h)
During the ACUTE phase, aldosterone activates signal transduction motifs which stimulate
ENaC activity
Many of the acute actions of aldosterone are believed to be
Non-genomic (i.e. do not change gene transcription)
The acute effects of aldosterone on ENaC results in
Increased Na+ reabsorption through this channel
Involves an up-regulation in the expression of ENaC and Na+/K+ ATPase proteins, and their import into the principal cell plasma membranes
The chronic effects of Aldosterone
Trades Na+ reabsorption for K+ secretion within the distal nephron
Aldosterone
By conserving Na+, aldosterone maintains body Na+ content and builds a favorable osmotic gradient for
-the way aldosterone combats volume depletion
H2O reabsorption
During volume depletion, the RAAS is mobilized, and together An-II and aldosterone induce Na+ reabsorption by actions within the
- ) Proximal nephron (An-II via NHE3)
2. ) Distal nephron (An-II via NCC and aldosterone via NCC and ENaC)
Whereas in the event of euvolemic hyperkalemia, excessive K+ causes changes within the distal nephron of which aldosterone sensitive kinases?
WNK1, WNK4, and SGK1
Recall that K+ increases aldosterone secretion without a rise in
An-II
This occurs via direct stimulation of adrenal zona glomerulosa cells by
K+
Thus, in the absence of An-II, aldosterone increases ROMK activity resulting in a more profoud effect on promoting
K+ secretion over Na+ reabsorption
Occurs as aldosterone-induced colume expansion proceeds
Pressure natriuresis (urinary excretion of Na_)
Pressure natriuresis is an increase in the excretion of Na+ and H2O in order to compensate for
Volume expansion (i.e. elevated MAP)
This renal counter measure (pressure natriuresis) to aldosterone dependent Na+ retention is known as
Aldosterone escape
Because of this escape, we can say that patients with the pathologic state of hyperaldosteronism are not generally
Hypernatremic (but are often hypokalemic)
Within a few minutes of elevated or decreased BP, e see activation of the
RAAS vasoconstrictor component
Activation of the RAAS vasoconstrictor component is followed by fluid shifts between
Extra- and intravascular volumes (within hours)
Within days of BP changes, we see
Hormone-mediated changes in renal volume conservation/elimination
Has vascular volume contributions of diuresis, antidiuresis w/ Na+ conservation (supported by An-II, aldosterone, and AVP), and vasomotor control
RAAS
Innervate the afferent and efferent arterioles, JG apparatus, and basement membrane of tubule. This exerting control over GFR as well as volume and composition of excreted urine
SNS fibers
