Regulation of Na and water excretion
3-way Control of renin secretion
A 3rd detection mechanism for the control of renin release is a component of the juxtaglomerular apparatus (JGA) that monitors the amount of tubular sodium chloride bathing the macula densa cells
With excessive Na+ loss
(e.g. sweating) the ECF volume contracts and renal perfusion pressure drops causing the GFR to drop and the GT balance prevents additional Na+ loss (proximal tubule excretes Na+ and water)
higher medullary renal blood flow
(has less autoregulation than cortex) increases interstitial hydrostatic pressure. Intra-renal signals command proximal tubule cells to reduce their transport capabilities. Hence Na+ reabsorption is decreased, excretion increased
Renal effects on cardiovascular system
**Concept: Kidneys affects the cardiovascular system by production of erythropoietin (RBC production, oxygen delivery and blood volume), by their control of salt and water excretion (which affects blood pressure), and by angiotensin II (which affects TPR)
3 mechanisms regulate renin secretion:
1) renal SNS, Beta-1 receptors on granular cells of afferent arterioles to stim renin secretion; 2) granular cells acting as intrarenal baroreceptors , their deformation alters renin secretion (decrease pressure, increase renin released; and 3) macula densa cells in thick ascending limb sense delivery of tubular sodium chloride, leading to release of transmitters that alter renin secretion from granular cells.(when sodium chloride delivery increases, renin production decreases)---another negative feedback system
Na+ excretion is regulated by:
1) renal hemodynamics alter the sodium load presented to the kidney and the process of NaCl reabsorption by glomerular tubular (GT) balance 2) regulating the effective circulating volume, affecting natriuresis (e.g. cardiopulmonary reflexes) 3) natriuretic humoral factors
Tubular lumen factors:
1. Increased flow (volumetric) in the proximal tubule leads to increased fluid and NaCl reabsorption 2. The luminal concentrations of solutes (e.g. glucose) and Na+- coupled solutes decrease along the length of the proximal tubule as it reabsorbs these solutes for return to the circulation 3. Secondly, there is also a proximal tubule flow censor causing increased fluid reabsorption 4. Thirdly, Angiotensin II (AII) increases Na+ reabsorption in the proximal tubule
Four parallel pathways that regulate effective circulating volume, all modulate Na+ reabsorption
1. Renin-angiotensin-aldosterone cascade (axis) often abbreviated as RAS 2. Sympathetic nervous system 3. Arginine vasopressin (antidiuretic hormone) 4. Atrial natriuretic peptide
Peritubular factors:
1. Starling Law of Transcapillary Exchange applies to peritubular capillaries and their uptake of interstitial fluid (reabsorption of NaCl and fluid from tubules) 2. Solutes and water enter the proximal tubule cell and exit into the interstitial space (reabsorption), then are taken up by peritubular capillaries 3. GT balance comes into play when changes in GFR affect filtration fraction (FF= GFR/RPF)
Summary of Angiotensin II actions
1. Stimulation of aldosterone release from glomerulosa cells of adrenal cortex (Boron Chapter 50) 2. Vasoconstriction of renal and other systemic vessels (enhances Na+ reabsorption by altering renal hemodynamics) 3. Enhances tubuloglomerular feedback (Boron Chapter 34) 4. Enhances Na-H exchange (promotes Na+ reabsorption in proximal tubule) 5. Renal hypertrophy of renal tubule cells 6. Stimulates thirst and release of AVP from posterior pituitary gland
In the kidney, AII overall causes sodium retention (reduced excretion) by binding to G-protein coupled receptors, initiating intracellular signaling:
1. constricting renal arterioles (efferent arterioles preferentially), reducing RPF and increasing GFR 2. constricting glomerular mesangial cells and reducing GFR 3. stimulating Na+ reabsorption in proximal tubule
Pharmacological inhibition of ACE and angiotensin II receptor blockers are
2 common medical treatments for high blood pressure
ECF volume =
2x ECF Na+ content/ECF osmolality
vasoconstriction flow
Decrease in blood pressure > decrease in GFR > further vasoconstriction from neural baroreceptor reflex all lead to decrease in sodium excretion.
Because the body generally stabilizes osmolarity, any increase in extracellular Na+ content will increase
ECF volume
Blood volume is proportional to and affected by
ECF volume, which is tightly regulated and highly dependent on Na+ osmolality
increased GFR with constant RPF, therefore increased
FF [as with increased efferent arteriolar resistance and decreased afferent arteriolar resistance] leads to increased GFR > increased peritubular osmotic pressure > less blood flowing into efferent arteriole > decreasing hydrostatic pressure in peritubular capillaries > increased fluid transport into peritubular capillaries > greater absorption of fluid and NaCl
The amount of sodium chloride bathing the cells depends on the
GFR and the rate of Na+ reabsorption in the nephron elements preceding the macula densa
Total filtered Na per day =
GFR x PNa = 180 L/day x 145 mmol/L = 26,100 mmol/day
Effect of changes in GFR on urinary Na+ excretion
Glomerular-tubular balance is not a linear relationship *Concept: diuresis and Na+ excretion are interrelated;
Baroreceptor types affecting kidneys
Note the 3 sets of baroreceptors that are "detectors of Na+ ", affecting its renal excretion and the water that follows *These intra-renal baroreceptor responses regulate Na+ excretion Concept: there are 3 pressure or volume sensing systems that ultimately affect sodium and water balance (redundant feedback control systems)
Other mechanisms contribute to high circulating volume diuresis: e.g.
RAS is inhibited, reducing Na+ reabsorption
The redundancy of these 3 mechanisms of renin release show the importance of the ______
RAS system
Kidneys secrete the hormone erythropoietin, which stimulates
RBC production, which affects blood volume
Dependence of AVP (ADH) release on plasma osmolality
Sensors (osmoreceptors) in the hypothalamus detect plasma osmolality High osmolality in blood results in greater release of AVP from posterior pituitary, and anti-diuresis, reduced water loss and restoration of osmolality to normal ( ~ 300 mOsm this response is also affected by the blood volume, curves green and blue Another feedback control mechanism; review the controlled parameter, detector, comparator, effector and feedback **Concept: at normal blood volume, the plasma levels (release) of AVP is linearly related to plasma osmolality; as osmolality increases in the plasma, more AVP is released from posterior pituitary
natriuretic peptides control sodium balance
There are several other renal mechanisms for controlling Na+ balance independent of water balance, control; under normal physiological conditions, none are as important as aldosterone
RAS AND EFFECTIVE CIRCULATING VOLUME
This flow chart (review from CVRH) shows the disturbance, and identifies negative feedback but does not directly show the angiotensin II vasoconstrictor effect that will affect the GFR *negative feedback is at the top right Concept: activation of RAS decreases sodium and water excretion, hence blood volume increases, hence arterial pressure increases
Pressure natriuresis and diuresis
This mechanism can be overridden by external signals. If ECF volume is low and renal arterial pressure increases there is much less salt and water loss (volume is preserved). Another example of override is during exercise when arterial pressure increases but sodium excretion decreases Summarizing, MOST of the time water accompanies sodium, but it is not always true. The kidney has INDEPENDENT control of salt and water that take place beyond the proximal tubule and loop of Henle----namely in collecting tubules and ducts and the chief player in this is aldosterone
estimates of renal handling of Na2+ along the nephron
Yellow boxes: absolute amounts of Na+ and the amount remaining of the filtered load Green boxes: fraction of the filtered load that remains in the lumen Na+ and Cl- reabsorption is largest in the proximal tubule, followed by Henle's loop The tubule reabsorbs Na+ by transcellular (e.g. coupled co-transporters) and paracellular paths
Extracellular Na+ content =
[Na+]O x ECF volume = (osmolality) x ECF volume
At low GFR the kidney excretes
a small amount of Na+ since the distal tubule continues to reabsorb Na+
Two of three mechanisms of renin secretion:
a) (rapidly and slowly acting) neurally-mediated baroreceptors > renal sympathetic nerves (ß1 ) > granular cells > renin release and vasoconstriction at the same time; b) (slower responding) granule cells releasing renin in response to low afferent arteriolar pressure
Kidneys work together with the cardiovascular system so:
a) there is enough blood volume to fill the vascular compartment; b) there is sufficient driving pressure for the blood; c) that blood and cells in the body have the proper osmolarity
Additionally AII inhibits renin production by
acting directly on the granular cells
The percentage of Na+ reabsorption dependent on
aldosterone is ~ 2% of the filtered load, therefore in presence of aldosterone, virtually no Na+ would be excreted
Aldosterone increases the genetic expression of
apical membrane Na+ channels and basolateral membrane Na, K-ATPase pumps to promote Na+ reabsorption
Several processes result in
autoregulation of both RBF and GFR: a) typical myogenic/metabolic response shown below; b) tubuloglomerular feedback, which is associated with the macula densa sodium chloride detector
In addition to "regular" vascular autonomic innervation of renal arterioles, there is the
baroreceptor mediated sympathetic innervation of the juxtaglomerular (granular) cells that regulates afferent arterioles, water and sodium balance
This retention of sodium corrects
deficits in body Na+, blood pressure and blood volume
AII has
direct tubular actions and stimulates the secretion of aldosterone from adrenal cortex
The main stimulus for release of ANP is
distension of the atria, which occurs during plasma volume expansion; this is a hormone released from the atrial tissue that acts on the nephron
Stretch mechanoreceptors ultimately send signals to the
dominant effector organ, the kidney, to change the rate of Na+ reabsorption or excretion in urine
mannitol is used to
draw water out of brain tissue (high intracranial pressure) *use of mannitol to wash out radiocontrast dye molecules to prevent renal toxicity
The parameter that the body regulates is the
effective circulating volume, which is defined as the functional volume that reflects the extent of tissue perfusion
If blood pressure is high, GFR is
elevated, filtered load of Na+ is increased , and this results in pressure diuresis (greater urine production) (e.g. outside on cold day with cold-pressor response)
Water diuresis
excretion of large volumes of urine that is dilute (poor in solutes)
Glomerular tubular balance stabilizes
fractional Na+ reabsorption by proximal tubule *Concept: Proximal tubules reabsorb a constant fraction of the filtered load of Na2+ ; proximal tubules can also conserve Na2+ (and therefor water) by reabsorbing it where it is picked up by peritubular capillaries into the systemic circulation.
ANP dilates
glomerular afferent arterioles, inhibits release of renin, inhibit actions of AII and acts in the medullary collecting duct to inhibit Na+ resorption
This constancy of Na+ reabsorption along the proximal tubule is the
glomerular tubular balance (GT Balance) and is independent of external neural and hormonal control; GT balance safeguards Na+ homeostasis
natriuretic peptides are greatly increased in patients with
heart failure and can serve as diagnostic biomarkers
If regulatory changes in renal blood flow (RBF) or GFR are too large, they would
impair the regulation of Na+ excretion and pathophysiological changes might occur **Therefore autoregulation of renal blood flow is important
If Na+ increases, then renin release is ______
inhibited
Tubuloglomerular feedback
involving purinergic receptors, nitric oxide and adenosine but in summary: high salt content in the thick ascending limb of a nephron generates signals that reduce GFR and filtration in that neuron, blunting the Na+ excretion initiated by other mechanisms, in which the appropriate overall response is increased Na+ excretion The same signals that reduce filtration also reduce renin secretion
Many RAS systems
kidney, heart and brain
Extracellular fluid (ECF) volume is affected by the
kidneys by filtration of fluid that can be excreted or resorbed
AI is converted to AII by angiotensin converting enzyme (ACE) which is expressed on the
luminal surface of endothelial cells in much of the whole vascular system
In response to increased osmolality in blood
AVP release reduces water loss in the nephrons, increases blood volume and decreases osmolality
autoregulation
Concept: autoregulation in the kidney is important for maintaining glomerular filtration mechanisms that affect Na+2 and water excretion
Autonomic control of renal function
Concept: direct stimulation of renal artery reduces RBF and may initiate release of renin with its cascade of effects; sympathoexcitation of granular cells also initiates the RAS cascade
Summary: control of Sodium excretion
Concept: sodium excretion is an important mechanism to control because of its role in osmolality for cell health, tissue functions and blood volume (cardiovascular effects); there are multiple redundant control mechanisms for sodium excretion
Low plasma volume response leading to increased aldosterone and reduced Na+ and water excretion
Concept: the 3-way production of renin has a contribution of sodium and water excretion by aldosterone; aldosterone is ultimately controlled by negative feedback control through the controlled release of renin
Renal blood flow (RBF) and glomerular filtration rate (GFR) regulate
sodium excretion; Many factors influence Na+ excretion but basically: the amount of Na+ excreted is the difference between the filtered load and the amount reabsorbed
Aldosterone, a steroid hormone, is a major stimulator of
sodium reabsorption (not water) in the distal nephron (beyond proximal tubule) where 90% of the Na+ has already been reabsorbed
osmotic diuresis and luminal sodium along the proximal tubule
Here blood and filtrate contain 40 mmol mannitol (300 mOsm) Reabsorption of NaCl from proximal tubule causes luminal mannitol to rise After this point there is no fluid absorption and osmotic diuresis occurs (mannitol obligatorily holds water in tubule) Concept: osmotic diuresis occurs when a poorly permeable substance remains in the tubule, obligatorily retaining water and thus, increasing urine volume.
Three humoral agents with natriuretic-like actions
In part due to inhibition of Na+ reabsorption in the tubule: 1. Endogenous Na-K pump inhibitor (a steroid in the plasma; high in patients with hypertension) 2. Prostaglandins and bradykinin 3. Dopamine All decrease Na+ reabsorption, causing natriuresis
Hemodynamic actions of AII, decreasing Na+ and water excretion
Involves vasoconstriction, the microcirculation, Starling's Law of Transcapillary exchange, and diffusion *Concept: AII has multiple mechanisms for raising arterial pressure, a renal mechanism of decreasing sodium and water excretion.
Kidneys limit
sodium-related changes in RBF and GFR that might otherwise reach damaging levels
Both ECF volume and arterial pressure exert control over
Na+ excretion
Increased pressure in renal artery increases
Na+ excretion---this pressure natriuresis increases water excretion also so it can be called pressure natriuresis and diuresis *These are totally intra-renal events. If the rapid arterial baroreceptor systems do not correct increases in arterial pressure, this backup control mechanism will restore arterial pressure
Renal detection of
Na+ is indirect, based on vascular pressures, by way of baroreceptors
The distal tubule also increases
Na+ reabsorption in response to increased flow (similar mechanism); if distal flow and GFR acutely fall (e.g. circulatory shock) then neural and humoral (e.g. aldosterone) influences can decrease luminal [Na+ ] further so that final urine may only contain traces of Na+
Aldosterone also stimulates
Na+ transport by other epithelia in the body—sweat, salivary ducts and the intestine- again moving Na+ out of the lumen into blood
Also sympathetic stimulation of the adrenal glands has an effect on
TPR and cardiac output from catecholamines.
The critical events that occur, responding to sensing by baroreceptors, lead to changes in
TPR and sodium excretion
If the low blood pressure persists,
renin is released and AII is produced and these also decrease sodium excretion
The macula densa can inhibit
renin release and reduce GFR and RBF we will learn in this presentation
There are two mechanisms for the release of AVP (ADH)
The first we learned about with the cardiopulmonary baroreceptors; low pressure "volume" receptors in response to "unloading" (reduced stretch) sent afferent signals to the hypothalamus causing release of ADH that increased blood volume The second mechanism of AVP release from posterior pituitary results from osmoreceptors in the hypothalamus that monitor circulating blood
Mechanism of aldosterone
The important controlling physiological factor of aldosterone is angiotensin II (inhibited by ANP) Concept: aldosterone cause reabsorption of Na+
Since AII is controlled by
renin, the importance of the RAS cascade is evident and prolonged stimulation by aldosterone requires continuous stimulation by renin
Intra-renal baroreceptors (new), initiate the
renin-angiotensin-aldosterone cascade, if renal perfusion pressure is low
Thus, sympathetic vasoconstriction of renal arteries and sympathetic stimulation of granular cells both have
secondary effects of increasing arterial pressure
However, the changes in Na+ excretion in response to sympathetic stimulation and consequential changes in blood volume are
much more important than the renal contribution to total peripheral resistance
The major detectors involved in the kidney's ability to regulate vascular resistance are the
neural baroreceptors and intrarenal baroreceptors
Juxtaglomerular (granular) cells are
non-neural, specialized cells in the JGA in the afferent arteriole, that regulate renal R; additionally granular cells are innervated by neurons from the vasomotor center to regulate renal R through the granular cells
The only time that [ Na+ ] does not change along the proximal tubule is with
osmotic diuresis, which occurs when there are poorly permeable substances in the plasma (e.g. diabetes mellitus and glucose)
The lower the percent of control (baseline), the lower the
percent of Na+ excretion (this non-linear relationship shows that small decreases in baseline GFR have large changes in Na+ excretion
AII is important in increasing
peripheral vascular resistance (decreasing GFR) but also is important in regulating Na+ reabsorption
Extracellular fluid volume (ECF) =
plasma volume + interstitial fluid volume
If the Na+ content of the body increases,
plasma volume increases and this leads to increased Na+ excretion
GFR is a capillary function of the
post/pre glomerular resistances and the arterial pressure
Angiotensin II is a
potent vasoconstrictor that causes several renal effects on Na+
Important is a family of hormones called natriuretic peptides that
promote sodium excretion in urine (atrial & brain natriuretic peptides, ANP and BNP) (main source is atrial)
Renin (released into the lumen of afferent arterioles) acts on
protein substrate angiotensinogen to produce angiotensin I (AI) that is converted to angiotensin II (AII)
Gt balance is achieved by the
proximal tubule using both peritubular and luminal factors
Anything that alters the GFR and therefore the Na+ load presented to the nephron, will see the
proximal tubules reabsorbing a constant fraction of the Na+ load
a major controller of GFR is
regulation of the filtered load by regulation of the GFR
Changes in resistance are a function of
the renal sympathetic nerve activity and levels of AII
Kidneys are a (small) part of the total peripheral resistance (TPR) and its
vasculature does respond to changes in sympathetic stimulation; vasoconstriction of renal artery reduces renal flow and, if sufficiently, kidneys will respond by: increasing the TPR through renin release and vasoconstriction by angiotensin II, and increase pressure by conserving Na+ and water (sympathetic nerve stimulation has multiple effects on kidneys)
Angiotensin II, a potent
vasoconstrictor, directly affects TPR, which affects arterial pressure, which affects renal perfusion