Hormonal Regulation of Kidney Function

Which hormone exerts a direct inhibitiory effect on renin secretion?

Angiotensin II (this is a negative feedback)

What are the actions of angiotensin II? (Don't try to go overboard and list the effects of these actions, just give the basic direct actions of angiotensin II)

Angiotensin II acts on the vascular system as a vasoconstrictor and stimulates adrenal production of aldosterone. It also acts within the kidneys to promote sodium reabsorption. (The diagram shows angiotensin II affecting the cardiovascular system by vasoconstriction and it acts on the adrenal cortex to stimulate release of aldosterone and on the kidneys themselves together these have the effect of increasing salt and H2O retention)

What stimulates the release of erythropoietin?

Decreased oxygen delivery to kidney (anemia, hypoxemia or inadequate renal blood flow)

Prostaglandins are derived from the metabolism of _____ ______

Arachidonic acid

What is the human form of ADH called?

Arginine vasopressin (AVP)

The half-life of ANP is 2-4 minutes, which part of the nephron is rich in degradative enzymes?

Brush border of the proximal tubule is rich in degradative enzymes

What stimulates the release of parathyroid hormone?

By low plasma Ca++ concentrations

Decreased activity of 1alpha-hydroxylase favors C-_____ hydroxylation and formation of the less active ________.

C-24 hydroxylation Less active 24,25(OH)2D

The most active form of vitamin D is ________

Calcitriol

Receptors that detect the reduce effective circulating volume are located in the __________, changes in the parasympathetic afferent firing rate will influence both the __________center as well as the release of ADH

Carotid sinus Vasomotor center

Central diabetes insipidus (also called pituitary or neurogenic diabetes insipidus) is characterized by what?

Decreases secretion of ADH

Central diabetes insipidus occurs most commonly following what?

It occurs most commonly after head trauma and with brain neoplasms or infection

What is the action of prostaglandins?

LOCAL intrarenal vasodilation

Mechanism of action of aldosterone in principal cells The aldosterone-induced proteins include factors that regulate the luminal _____ and ______ and components of the _________. There is also evidence for rapid membrane effects of aldosterone on tubular cells.

Luminal Na+ and K+ channels and components of the Na+-K+-ATPase pump

40% of A I conversion to A II occurs in the ________

Lungs

What is the half life of angiotensin II?

1-3 minutes

What are the two types of diabetes insipidus?

1. Central diabetes insipidus (also called pituitary or neurogenic diabetes insipidus) 2. Nephrogenic diabetes insipidus

What is the control of renin secretion?

1. Decreased blood pressure or extracellular volume due to intrarenal baroreceptors: arterioles of the JGA, direct myogenic response 2. Decreased delivery of NaCl and tubular fluid volume to the early distal tubule of the macula densa cells in the juxtaglomerular apparatus causes a systemic release of renin 3. Increased sympathetic nervous system activity 4. Angiotensin II exerts a direct inhibitory effect on renin secretion (negative feedback)

Actions of angiotensin II: How does angiotensin II promote Na+ and water retention which expands plasma volume

1. Direct stimulation of Na+ reabsorption in the proximal tubule 2. Indirect by stimulating aldosterone secretion from the adrenal cortex 3. Stimulates the release of ADH and increases thirst

Locations: prostaglandins Prostaglandins are produced in a number of sites in the kidney including what?

1. Glomerular and vascular endothelium 2. Medullary and cortical collecting tubule cells = main site of synthesis 3. Renomedullary cells

What are the factor that stimulate the release of aldosterone?

1. Increased Angiotensin II (primary regulator) 2. Increased leveled of ACTH (adrenocorticotropic hormone) 3. Increases potassium in plasma

Release: ADH What are the two major stimuli that cause ADH secretion?

1. Increased hyperosmolarity 2. Depletion of effective circulating volume

What are the actions of vitamin D?

1. Increases intestinal absorption of calcium and phosphate (major effect) 2. Decrease release of PTH (form parathyroid gland) 3. Increase bone resorption 4. Kidney: increase calcium reabsorption The overall affect is to increase the plasma Ca2+ concentration

What are the two general categories of actions of angiotensin II?

1. Promotes renal Na+ and water retention which expands plasma volume 2. Reacts with angiotensin receptors on vascular smooth muscle to promote vasoconstriction (mediated by calcium uptake into the cells) and increased blood pressure

What are the actions of ADH?

1. Stimulation of V2 receptors of the principal cells: increase in water reabsorption 2. Stimulation of V1 receptors on renal and systemic vasculature: vasoconstriction

What are the actions of ANP?

1. Vascular relaxation 2. Diuresis and natriuresis

What are the actions of bradykinin?

1. Vasodilation: counteracts the effect of renal vasoconstriction, minimizing the extent of renal ischemia 2. Natriuresis and diuresis

The half-life of ANP is _______ minutes.

2-4 minutes

What is another name for provitamin D?

7-dehydrocholesterol

Control of Renin Secretion A decrease in arterial blood pressure _______ renin secretion by what mechanism? (Just the mechanisms within the kidney itself)

A decrease in arterial blood pressure increases renin secretion by both the intrarenal baroreceptors and macula densa receptors 1. A decrease in the arterial pressure results in a decrease in the stretch of granular cells (intrarenal receptors) which leads to increased renin secretion 2. A decrease in the arterial pressure results in a decrease in the GFR, which leads to decrease in the rate of fluid delivery to the macula densa, which leads to decreased Na and Cl concentrations in the macula dense fluid, which results in decreased reabsorption of Na and Cl by macula densa cells which leads to an increae in the renin secretion

Which of the regulators of aldosterone release that stimulates its release is not a critical regulator and effect is transitory?

ACTH (adreoncorticotropic hormone)

What are the actions of the parathyroid hormone and what is their overall effect?

Actions: increase plasma calcium concentration 1 bone resorption 2. Renal effects: A. Promotes calcitriol (active form of vitamin D) formation in the kidney B. Increases Ca++ reabsorption C. Increases phosphate excretion

What is the action of erythropoietin?

Acts on erythroid precursor cells in bone marrow to increase erythropoiesis

Angiotensin II (A II) is an octapeptide split from ________ by __________ located in the _______

Angiotensin II (A II) is an octapeptide split from angiotensin I by angiotensin-converting enzyme located in the lungs

The aldosterone acts on intercalated cells to cause what effects?

Aldosterone promotes H+ secretion

The aldosterone acts on cortical and medullary collecting duct *principal cells to cause what effect?

Aldosterone promotes protein synthesis 1. Na+ and K+ channels (luminal side) 2. Na+-K+-ATPase enzymes (basolateral border)

Release: aldosterone The primary regulation of aldosterone release is by increased __________

Angiotensin II

What is the affect of angiotensin II on filtration fraction?

Angiotensin II (50 times more potent than norepinephrine) reacts with angiotensin receptors on vascular smooth muscle to promote vasoconstriction. This includes vasoconstriction of both afferent and efferent glomerular arterioles. This causes a decrease in the renal blood flow that is greater than a decrease in GFR so there is an increase in the FF (In the previous lecture we learned that this increases the plasma oncotic pressure in the peritublar capillary which decreases the RIHP that promotes sodium and water reabsorption so this is another way. That it can promote sodium and water retention I think - not listed in notes)

Which has a more potent affect on vascular smooth muscle, angiotensin II or norepinephrine?

Angiotensin II is 50 time more potent than norepinephirne

What does ADH stand for?

Antidiuretic hormone

The nephrogenic diabetes insipidus can result from a number of systemic disorders and, more rarely from inherited disorder. Many of these acquired forms of this condition are the result of decreased expression of ___________ in the collecting duct

Aquaporin 2 (AQP2)

What is nephrogenic diabetes insipidus characterized by?

Characterized by a decrease in the ability to concentrate urine due to resistance to ADH action in the kidney.

Location: ADH The _______ system responds to ADH within a few minutes.

Collecting tubule system

Mechanism of Action of aldosterone in principal cells In circulation, aldosterone is mainly bound to ____________ or _______.

Cortisol-binding globulin (CBG) or albumin

What is the functional significance of the local intrarenal vasodilation caused by prostaglandins?

Counteract effect of renal vasoconstriction, minimizes extend of renal ischemia

Diabetes insipidus: is a disorder characterized by what?

Disorder characterized by intense thirst and by the excretion of large amount of diluted urine (polyuria), as much as 25 L/day

Cholecalciferol and ergocalciferol (from ______) are transported to the ______, whey they undergo the first step in bioactivation, the hydroxilation of ________.

Ergocalciferol (from plants) Transported to the liver, where they undergo the first step in bioactivation, the hydroxilation of C-25 to 25-hydroxyvitamin D (25(OH)D)

T or F: the baroreceptors that detect the decrease in effective circulating volume are more sensitive than the osmorecepotrs

FALSE: not as sensitive as osmoreceptors, need 5-10% change in volume to get a response, however the system then responds with a marked release of ADH

T or F: the osmorecepotrs in the hypothalamus are not very sensitive

FALSE: the osmoreceptors in the hypothalamus are very sensitive to changes as small as 1% (e.g. drinking 500 mL of water). They are very sensitive to solutes that are non-permeable (i.e. NaCl)

Vitamin D Production: T or F: vitamin D3 (or cholecalciferol) is active

False Vitamin D3 is inactive

T or F: the effect of aldosterone on K+ excretion would also diminish with prolonged treatment with aldosterone/mineralocorticoids.

False: the effect of K+ excretion is sustained throughout the

T or F: vitamin D is one of the water soluble vitamins

False: vitamin D is a fat soluble steroid

**look at the flow chart diagram on angiotensin II that summarizes all of its effect on page 6

It mentions some factors like the affect on he sympathetic nervous system that weren't listed in her notes and goes into more detail about its affect on the brain

What type of hormone is erythropoietin?

Glycoproteins growth factor

Atrial Natriuretic peptide (ANP): location Where is the ANP located?

Granules in atrial myocytes, particular in the right atrium

The angiotensin II has a half life of 1-3 minutes and then it is converted to a heptapeptide, ___________, that has only a quarter of the pressure effect of A II but the same ability to do what?

Heptapeptide, angiotensin III, which has a quarter of the presser effect of A II but the same ability to promote production and secretion of aldosterone

Why is ADH also called vasopressin?

High concentrations of ADH exert direct vasoconstriction of arteriolar smooth muscle which increases TPR (total peripheral resistance) thus increases arterial blood pressure (reason it is called vasopressin)

Release:ADH Osmoreceptors in the _______ respond to increase in Posm (essential PNa+)

Hypothalamus

With administration of aldosterone, what is the immediate affect on urinary sodium excretion, extracellular fluid volume and mean arterial pressure? And what is the effect over a period of days? (What happens when the aldosterone treatment is removed?)

Immediate effect is a decrease in the urinary sodium excretion, increased ECF volume, and an increase in blood pressure The urinary sodium excretion returns to normal after a couple of days but the ECF volume remains high which is what causes a continual increase in the blood pressure (see graph on slide 16) (With the removal of aldosterone the urinary sodium excretion increases for a little bit and then the blood pressure goes back to normal and the ECF volume goes back to normal)

What are the actions of aldosterone?

Increased Na+ and Cl- reabsorption Increased K+ and H+ secretion

What triggers the release of ANP from the granules in the atrial myocytes?

Increased by atrial stretch in hypervolemic states

What is the downstream affect of the binding of ADH to V2 receptors on the principal cells along the basolateral border of the renal cortical and medullary collecting ducts?

Increased number of luminal water channels causes an increase in water reabsorption from tubule to peritubular space (provided there is an osmotic gradient) which ultimately results in an increase in the extracellular fluid volume

What is the affect, if any, of ADH on vascular resistance?

Increased vascular resistance due to its action on V1 receptors of the renal and systemic vasculature

How does the extracellular fluid compartment change with increased secretion of ADH?

Increases the extracellular fluid volume

Location of Angiotensin II The active peptide is located in the systemic circulation and can be produced __________

Intrarenally

Aldosterone belongs to what class of hormones?

Mineralocorticoid (Or at least I think this is the class of hormone it could be another name for it? ) It is also listed as adrenocrotical steroid

Mechanism of action of aldosterone in principal cells The free aldosterone enters the principal cells of the kidney and binds to the ____________ receptor

Mineralocorticoid receptor (notice that it enters the cell before binding to receptor, this is an intracellular receptor)

Infusion of PGE2 or I2 results in _______ and _______

Natriuresis and diuresis

Which class of drugs inhibits PG synthesis?

Non-steroidal anti-inflammatory drugs

What is the affect of non-steroidal anti-inflammatory drugs on the kidneys in the case of hypovolemic disorder?

Non-steroidal anti-inflammatory drugs (inhibitor of PG synthesis) can end to reversible renal ischemia in hypovolemic disorder

________ is a major renal prostaglandin, however, kidney can also produce _________, _______, _______, and ______.

PGE2 is the major renal prostaglandin, however, kidney can also produce PGF2alpha, PGD2, thromboxane A2, and prostacyclin

The production of vitamin D is stimulated by what?

PTH (parathyroid hormone) acting on kidneys And hypophosphatemia I think???

PTH (parathyroid hormone) is a polypeptide secreted from the ___________ in response to what?

Parathyroid glands in response to a fall in plasma concentration of ionized Ca++

Atrial natriuretic peptide (ANP) is a 28 amino acid __________. (What type of hormone?)

Peptide

Where is the major site of production of erythropoietin?

Peritubular capillary endothelial cell major site of production (<10% from liver)

Bradykinin is produced by cells within the kidney. In plasma, bradykinin is also produced by the action of __________

Plasma kallikrein

What type of hormone is parathyroid hormone?

Polypeptide

The ADH is formed in the supraoptic and paraventicular nuclei in the hypothalamus and then secretory granules containing ADH are stored in the _____ _____ for subsequent release

Posterior pituitary

Where is the parathyroid hormone produced?

Produced in the parathyroid glands

Location: aldosterone Where is aldosterone produced?

Produced in the zona glomerulosa of the adrenal cortex

Local production of _______ in the kidney decreases the rise of renal vascular resistance in the presence of ADH and maintain renal perfusion.

Prostaglandins

What is the mechanism by which synthesis of prostaglandins can result in the inhibition of renal water reabsorption?

Prostaglandins stimulate the V2 receptor membrane bound Gi protein which inhibits adenylate cyclase production of cAMP and decreases the number of water channels in the collecting duct

Provitamin D (7-dehydrocholesterol) in the _______ is converted to _________ by ________.

Provitamin D (7-dehydrocholesterol) in the skin is converted to cholecalciferol by ultraviolet light.

Mechanism of action of aldosterone in principal cells The binding of the aldosterone to the minderalocorticoid receptor (MR) induces release of a ___________, _______ to two MRs and _________ to the nucleus where it binds to a glucocorticoid response element (GRE) on the DNA, and along with other transcription factors, initiates protein synthesis.

Release of heat shock protein (hsp), dimerization of two MRs, and translocation to the nucleus

One of the actions of ANP is natriuresis and diuresis What are the renal effects that produce this and what are the extrarenal effects that produce this?

Renal effects: 1. Inhibits Na+ reabsorption in the proximal tubule and cortical and medullary collecting ducts (dopamine necessary for proximal tubule effect) 2. Inhibits ADH dependent water reabsorption 3. Hyperfiltration - vasodilation of preglomerular arteries - increases GFR and FF which results in increased FE of sodium 4. Inhibits renin release which decreases angiotensin II formation Extrarenal effect: 1. Inhibits aldosterone biosynthesis in adrenal gland 2. Inhibit vasopressin (ADH) secretion centrally

What are the hormones involved in the hormonal regulation of the kidneys?

Renin Angiotensin II Prostaglandins Bradykinin ADH Aldosterone ANP Vitamin D PTH Erythropoietin

Release of angiotensin II: The concentration of circulating A II is directly related to the level of ________ in the systemic circulation

Renin (so this is the rate limiting enzyme)

Renin is a hormone that is in a system with what other two hormones?

Renin-angiotensin-aldosterone system

Aldosterone escape is due to a rise in the _________ which effectively _______ Na+ reabsorption in proximal tubule.

Rise in ECF volume which effectively decreases Na+ reabsorption in proximal tubule

Prolonged treatment with mineralocorticoids /aldosterone results in brief period of _______ retention but only lasts a few days

Salt

Renin is secreted by what cells?

Secreted by granular cells (juxtaglomerular cells "JG" cells)

So her objectives state that we should know the site of production, control of secretion, and actions of the hormones listed in the objectives

So focus on these features when studying each hormone

The activity of 1alpha-hydroxylase is stimulated by _______, and inhibited by _________.

Stimulated by PTH Inhibited by calcium levels and 1,25(OH)2D

Stimulation of ______ receptors by ADH of the principal cells along the basolateral border of the renal cortical and medullary collecting ducts causes an increase in _____ ______activity.

Stimulation of V2 receptors Increases adenylaste cyclase activity

Stimulation of renal prostaglandin synthesis _______ renal water reabsorption and vasoconstriction. (Inhibits or stimulates)

Stimulation of renal prostaglandin synthesis inhibits renal water reabsorption and vasoconstriction

Location: ADH The ADH is formed in the _______ and _______ nuclei of the hypothalamus

Supraoptic and paraventricular nuclei of the hypothalamus

Syndrome of inappropriate ADH secretion (SIADH): _______ patients have a persistant rise in ADH due to stress/pain response, can lead to water ________ with _______ if free water is administered to these patients

Surgical patients have a persistant rise in ADH due to stress/pain response, can lead to water retention with hyponatremai if free water is administered to post-op patients Review: post-op SIADH was one of the things that could lead to hyposmotic overhydration water shift (along with pure water IV or 5% glucose IV) which results in an increase in volume of both ECF and ICF with a decrease in the vertical line

What does SIADH stand for?

Syndrome of inappropriate ADH secretion (SIADH)

Location: ADH The ADH is rapidly metabolize in the ____ and ______, half-life in plasma only _______ minutes.

The ADH is rapidly metabolized in the liver and kidney, half-life in plasma is only 15-20 minutes

The granular cells (juxtaglomerular cells) are specialized _________ cells in the wall of what?

The granular cells (juxtaglomerular cells) are specialized smooth muscle cells in the wall of the glomerular arterioles (particularly the afferent) of the JGA (juxtaglomerular apparatus)

Describe the components of the global renin-angiotensin-aldosterone system and what is the ultimate effect of this system

The liver produces the precursor angiotensinogen. The stimuli to the kidney increase production of renin which is an enzyme that converts the angiotensinogen to angiotensin I I think by a cleavage reaction that shortens this polypeptide from 453 amino acids to 10 amino acids. The angiotensin I is converted to angiotensin II by angiotensin-converting enzymes in the endothelium. The angiotensin II acts on the cardiovascular system to stimulate vasoconstriction and acts on the adrenal glands to stimulate production of aldosterone and on the kidneys themselves to increase sodium rebaroptin which increases both sodium and water reabsorption. The vasoconstrictor affect along with the salt and H2O retention results in an overall effect of the increasing the blood pressure.

Control of Renin secretion The renal sympathetic nerves ________ renin secretion by a direct effect on the granular cells (mediated by _____-adrenergic receptors) and by what other effect? (Give the flow chart diagram info on how sympathetic nerves control rening secretion)

The renal sympathetic nerves increase renin secretion by a direct effect on the granular cells (mediated by beta1-adrenergic receptors) and by causing a decrease in flow to the macula densa Increased activity of the renal sympathetic nerves results in a decrease in the GFR and increased proximal Na and H2O reabsorption both of which have the affect of decreasing the rate of fluid delivery to the macula densa which leads to increased renin secretion The sympathetic nervous system also has a direct stimulation of granular cells (beta1-adrenergic receptors) to increase renin secretion

The second hydroxylation step at ______, occurs in the ______ and results in hormonal active _______.

The second hydroxylation step, at C-1, occurs in the kidney and result in the hromonally active 1,25(OH)2D.

This activation step for vitamin D production, mediated by __________ (enzyme), is undertight regulation by the ________, _______ levels and ________.

This activation step for vitamin D production mediated by 1alpha-hydroxylase is under tight regulation by parathyroid hormone (PTH), calcium level, and 1,25 (OH)2D

T or F: ADH is a nonapeptide

True

T or F: emotional stresses, neuropsychiatric disorder, as well as a number of drugs also affect ADH secretion.

True

T or F: the 25-hydroxyvitamin D (25(OH)D) is the major circulating form of vitamin D

True

T or F: volume depletion even in the presence of low Posm will cause ADH release

True depletion of effective circulating volume is one of the stimuli that causes ADH secretion

T or F: the sensitivity of aldosterone release to increased plasma potassium is high

True: is is very sensitive, rise of 0.1 to 0.2 mEq/L in K+ will cause release

T or F: the prostaglandins have little systemic activity

True: the prostaglandins have little systemic activity since they are rapidly metabolized in the lung

ADH stimulation of ______ receptors on renal and systemic vasculature causes __________ turnover and vasoconstriction.

V1 receptors Phosphatidylinositol turnover

How does vasoconstriction result in an increased production of prostaglandins?

Vasoactive hormones activate membrane phosphatidylinositol turnover which leads to production of DAG (diacylglycerol) which contains arachidonic acid

Production: prostaglandins Prostaglandin synthesis is increased by what?

Vasoconstriction (angiotensin II, norepinephrine, and vasopressin [ADH])

Vitamin D production: Vitamin D3 is inactive, what steps does it undergo to become activated?

Vit D2 is inactive. It is hydroxylated in the position 25 by the liver and then in the position 1 by the proximal tubular cells in the kidney to form the active compound 1,25-dihydroxyvitamin D3

Vitamin D Production: Vitamin D3 (or _________) is formed by the action of __________ on 7-dehydrocholoesterol in the skin. Is is also found in food.

Vitamin D3 (or cholecalciferol) is formed by the action of ultraviolet radiation on 7-dehydrocholesterol in the skin. It is also found in food.

_________ movement out of the osmoreceptor cell will cause secretion of ADH.

Water movement out of the osmoreceptor cell will cause secretion of ADH

How can we correct central diabetes insipidus?

With the administration of exogenous ADH