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