Renal: 1:00 - 2:00 Scribe: Marjorie Hannon

Renal: 1:00 - 2:00 Scribe: Marjorie Hannon

Monday, May 11, 2009 Proof: Caitlin Cox

Dr. Schafer Control of Sodium Page 5 of 5

BP = Blood Pressure ECF = Extracellular Fluid Volume JG = Juxtaglomerular

ANP = Atrial natriuretic peptide GFR = Glomerular Filtration Rate

I.  Renal Physiology—Lecture #6 [S2]

a.  First we will talk about sodium balance. On Friday (2nd lecture), we talked about the how the job of the kidney is largely to regulate the salt output to equal the amount of salt intake per day. This is an extremely important job because the amount of sodium you have in your body determines the extracellular fluid volume. The important part of the extracellular fluid volume is the plasma volume.

b.  The filling of the vascular system and the filling of the extracellular fluid is largely dependent on how much sodium you take in and how much of the sodium you retain.

c.  The extracellular fluid is directly proportional to the amount of sodium in the body.

d.  Therefore it is a very important thing to regulate because it is thought to be the most important determinant of the blood pressure, the mean arterial pressure.

e.  Expansion of extracellular fluid volume (particularly in salt-sensitive individuals) leads to higher blood pressure.

f.  One of the first things a physician may do to treat someone with high blood pressure is to get them to reduce their salt intake. If that isn’t working or if the person isn’t compliant, the physician may also add a diuretic to force the kidney to get rid of more sodium. That is the first line of attack to try and do something about high BP.

i.  In about 50% of the cases of new hypertension (in younger individuals that haven’t had it for a long period of time), the patient is responsive to reducing salt intake or using a diuretic.

ii.  This was important for pilots during war because they couldn’t take more powerful antihypertensive drugs that interfered with the sympathetic nervous system because they couldn’t be on flight status. It was very important to get their BP down using means other than sympathetic agents and one of the best ways was reducing salt intake and using diuretics.

g.  Hypertension is in large part a disease of an inability to properly regulate the body’s sodium.

i.  In at least half of the individuals with high BP, their high BP is a consequence of something driving their kidneys to retain too much salt, to expand the ECF, to raise vascular filling, raise venous return to the heart, and thereby increase BP.

h.  A lot of what we’ll talk about in the control of sodium balance has direct applicability to maintaining a normal BP.

i.  The first thing we will talk about is the renin angiotensin aldosterone system (RAS) in maintaining this sodium balance, ECF volume, and BP.

i.  Aldosterone is a hormone (produced by the adrenal cortex). It acts on the distal most part of the nephron to enhance sodium reabsorption and potassium secretion.

j.  Next we’ll talk about sites and amounts of sodium reabsorption.

k.  Then we will talk about where the renin-angiotensin-aldosterone (RAS) system acts.

l.  Next we will talk about something on the other side of the coin, a hormone released by the atria of the heart that acts as a natriurretic peptide that tends to drive increased sodium excretion rather than conserve sodium.

m.  Finally we will try to put it all together and understand how the body responds to hypo and hypervolemia (volume in terms of the ECF). Usually blood volume is hand in hand with change in ECF volume.

II.  The Juxtaglomerular apparatus [S3]

a.  First to the renin-angiotensin system. This is a schematic diagram of the juxtaglomerular apparatus.

b.  This is the glomerulus with its proximal tubule (on the top left corner). You can see sections of the glomerular capillaries. We see the afferent arteriole running in here and the efferent arteriole is running out from the glomerular capillaries.

c.  The important thing to remember is that right next to these vascular structures is the distal part of the nephron coming back to its own glomerulus in the region where there are some specialized cells called the macula densa cells. It is about the point where the thick ascending limb changes into the distal tubule.

d.  Remember that when you have too much sodium delivery, these cells swell up and release ATP and cause constriction of the afferent arteriole.

i.  This is the primary way that the tubule can regulate its own renal blood flow (each individual nephron) and can regulate its own glomerular filtration rate.

ii.  This mechanism is called tubulo-glomerular feedback.

e.  Another component of this system is the Juxtaglomerular cells (particularly in the afferent arteriole, but also in the efferent arteriole to some extent).

i.  They store secretory granules (called the granular cells of the juxtaglomerular apparatus). They are vascular smooth muscle cells, like in most arterioles.

ii.  The secretory granules are of the hormone renin. This hormone is produced by the kidney and is important in sodium balance, ECF volume, and control of BP.

iii.  Renin can be released from the juxtaglomerular cells in response to a number of stimuli. For example:

1.  Low blood pressure- when the afferent arteriole isn’t getting perfused well so that blood flow or pressure is down

2.  Sympathetic efferent nerves- the nerves control the resistance of the efferent and afferent arterioles.

3.  Circulating catecholamines

4.  Low sodium delivery- if the glomeruli aren’t filtering well because there is not adequate pressure and flow coming in

III.  Flow Chart: Renin [S4] What does renin do and how does this hormone act in the body?

a.  The JG cells have the capacity to release renin.

i.  The hormone renin can circulate throughout the body, but this release of renin from the JG cells in the juxtaglomerular apparatus is the rate limiting step.

b.  What does renin do?

i.  Throughout the body it acts upon a renin substrate. The substrate is angiotensinogen (an alpha 2 globulin—you don’t need to know this). This globulin is normally produced by the liver, and then circulates. Renin acts like a protease that cleaves off a decapeptide (10 amino acids) called angiotensin 1.

ii.  Angiotensin 1 itself doesn’t have any activity, but in the plasma (particularly the lungs and the kidney), there is an enzyme called ACE (angiotensin converting enzyme). ACE knocks off another two amino acids from angiotensin 1 and forms angiotensin II (an octapeptide).

iii.  Angiotensin II mediates all of the effects that are started by the production of renin.

iv.  Angiotensin II can be further broken down by proteases (that is one way it is gotten rid of by the plasma) as well as being filtered and excreted by the kidney.

c.  Normal actions of angiotensin II:

i.  A direct vasoconstrictor. Operates throughout the circulation (not just in the kidney), all over the body, to increase the constriction of the resistance vessels and to raise total peripheral resistance; this increases blood pressure.

ii.  Stimulates the adrenal cortex to release the hormone aldosterone. Aldosterone acts on the distal parts of the nephron to decrease sodium excretion (causes renal sodium retention), and to increase ECF volume.

iii.  Has a direct effect on the proximal tubule to increase its rate of sodium reabsorption.

iv.  Therefore it acts indirectly via aldosterone to cause salt retention by the kidneys in the terminal region of the nephron. It also acts directly on proximal tubules to retain sodium. What is the net effect of all of this sodium retention and expansion of ECF volume?

1.  This will increase plasma volume

2.  Increase venous return- this causes increased cardiac output which contributes to a rise in the systemic arterial pressure.

v.  Two things are driving pressure up: the indirect effect of angiotensin II to cause salt retention and expansion of the ECF volume and the effects of angiotensin II directly to cause vasoconstriction throughout the body (including the afferent and efferent arterioles).

d.  This is why we call it the RAS system (it involves renin, angiotensin, and aldosterone)—sometimes called RAAS (for angiotensin and aldosterone). This is the heart of the system.

e.  An important way to combat hypertension is to interfere with the action of the RAS system in some way.

i.  For people with kidney failure (retain too much salt) and for people with diabetes mellitus (have high BP due to the diabetes and due to the effects of diabetes on the kidney, so called “diabetic renal disease”), interfering with this system is often very effective in improving kidney function and in counteracting their hypertension that the individuals have developed.

f.  What do these drugs do?

i.  ACE inhibitors- Some of the longest known inhibitors of this system (early 70s)

1.  Inhibit the angiotensin converting enzyme which prevents the breakdown of angiotensin 1. Renin isn’t going to have an effect because it can’t produce the active agent (angiotensin II).

2.  Very important antihypertension agents.

3.  They help the person excrete more salt and get rid of ECF volume.

ii.  Direct inhibitors of the actions of angiotensin 2

1.  Act by blocking the receptors for angiotensin II (AT1 and AT2 - there are selective inhibitors for both of these types receptors that are available)

g.  Angiotensin 2 has more effects than just the ones we’ve talked about. Concentrate on its effects in retaining salt and increasing total peripheral resistance. It also has significant effects on cardiac muscle (muscle remodeling in heart failure), and on the brain where it can promote thirst. You do not need to know these other effects, except to know that it is a widespread agent that acts on a number of organs in the body.

IV.  Flow Chart- JG cells [S5]

a.  What will cause the granular JG cells (found in the afferent arteriole and to a lesser extent in the efferent arteriole) to release renin and therefore cause all of the effects that we just talked about (in particular Angiotensin II affecting salt reabsorption, retaining fluid to increase ECF volume and pressure, and also the direct effects on increasing total peripheral resistance)? Logically they are the things that should be compensated by increased ECF volume and BP.

b.  Causes of renin release:

i.  Low blood pressure and low perfusion of the kidneys (due to a diminished plasma volume)

1.  This leads to a decrease in tension in the arteriole wall which leads to a fall in intracellular calcium that stimulates renin production and release.

ii.  Decreased extracellular fluid volume causes all of the organs to send signals to the brain that blood volume is low. This causes an activation of sympathetic nerve firing to the kidneys and it will also release circulating catecholamines.

1.  The sympathetic nerve endings and the catecholamines will stimulate a rise in intracellular cAMP which will lead to renin production.

iii.  Decreased delivery of salt to the macula densa region (the beginning of the distal convoluted tubule or the end of the thick ascending limb)

1.  [Add a down arrow to the “local release of ATP…” for decrease ATP in your notes].

2.  Will decrease local release of ATP (which we said would cause these cells to constrict).

3.  Decreased ATP due to decreased sodium delivery is a stimulus for renin release.

4.  Decreased delivery of salt to macula densa is generally a sign that you are not filtering enough salt, so the kidney responds as if there isn’t enough ECF volume or plasma volume (secretes renin).

V.  Na+ handling in the nephron [S6]: Where is the sodium being reabsorbed along the nephron?

a.  You filter over 25,000 millimoles of sodium per day, and you excrete less than 1% of what is filtered.

b.  Regulating how much is finally excreted is done by just making fine adjustments in the range of reabsorbing about 1.2 – 0.2%. Regulating that last 1% is crucial in maintaining body salt balance. This is because although you filter 25,000 millimoles of sodium per day, 150 millimoles of sodium plus its accompanying chloride is enough to make one liter of isotonic solution. If you retain 150 millimoles of extra sodium per day, you’ll expand your ECF volume by a liter. The last 1% is very crucial in regulating ECF volume.

c.  Where do you reabsorb the sodium?

i.  2/3 is being reabsorbed in the proximal tubule. We talked about the active mechanisms for sodium reabsorption (including the Tm limited mechanisms).

ii.  The thin segment of the ascending limb has passive reabsorption.

iii.  25% of the reabsorption is in the thick ascending limb is active reabsorption, by the NaK2CL co-transporter.

1.  This is the one that is sensitive to loop diuretics

iv.  When you reach the macula densa, there is only about 8% of the filtered salt that is left.

v.  About 5% is reabsorbed in the distal convoluted tubule by the NaCl co-transporter

1.  This one is sensitive to thiazide diuretics

vi.  The remainder (3%) is reabsorbed from the late part of the distal convoluted tubule and in the collecting duct. The sodium is reabsorbed via these sodium channels in the principle cells located in this region of the nephron (from the late convoluted tubule to the collecting duct).