Lecture 21 Flashcards
(25 cards)
What hormone is aldosterone and what role does it play? How does it function to play a role in such a process? What hormone is similar to aldosterone in function?
Aldosterone is the main mineralocorticoid hormone that regulates blood pressure. It increases the reabsorption of ions and water in the kidneys. It acts on the distal tubules and collecting ducts of the kidney nephron. As a result, increase in blood pressure and blood volume occurs. It’s similar to anti-diuretic hormone (vasopressin,) which causes reabsorption of water as a result of high plasma tonicity.
What occurs as a result of dysregulation of aldosterone?
Anytime that you have dysregulation with aldosterone, you can start to develop diseases like cardiovascular disease, renal disease, hypertension. Most people with hypertension have aldosterone issues.
How does absorption of solutes/fluid from arterioles into the nephron work? What happens after absorption occurs? Where does the filtrate head to? How/where is stuff reabsorbed in the nephrons?
Proximal tubule have specific transporters for things and will try to absorb specific things like glucose, ions, water, etc.
Henle’s Loop: reabsorption of water occurs as filtrate moves down the descending Loop of Henle. Since the concentration of ions has increased as a result of water reabsorption, ion reabsorption can occur as the filtrate moves up the ascending Loop of Henle.
As water is reabsorbed into the blood from the nephron, salt will be absorbed from the blood into the nephron.
As filtrate moves up the nephron, the filtrate will reach the distal tubule and then the collecting duct which will connect to the bladder. Some urea can go back into the blood from the collecting duct and the urea should stay there so it can get excreted.
What would happen if your kidneys fail? How much of your kidney is needed such that they are able to function properly? What would need to be done in order to make up for the filtration of your blood which is done by your kidneys?
We can’t filter our blood. Only half a kidney is required to be able to function and efficiently filter out blood. Dialysis will not mimic everything that the kidneys do but it would be able to mimic the filtration of waste that the kidneys take care of. It doesn’t replace all of the kidneys’ function but it’s a good start before needing a kidney replacement.
What is the purpose of the Renin-Angiotensin-Aldosterone System (RAAS) and how does this system work? Why is RAAS a multi-organ system and why is it important?
RAAS controls blood pressure through aldosterone (which will stimulate the kidneys to increase sodium reabsorption and increase potassium excretion.
Signal comes in, tells the body it needs to raise blood pressure/increase sodium. Angiotensinogen is released from the liver and goes through the blood. Renin (enzyme that cleaves angiotensinogen) is released from the kidneys so that angiotensinogen can be converted to angiotensin I. Angiotensin I goes to the lungs, where 2 AA is cleaved off by ACE (angiotensin cleavage enzyme) to make angiotensin II. Angiotensin II goes to the adrenal cortex and stimulates the production of aldosterone in zona glomerulosa and stimulates the kidneys to reabsorb more sodium/water to increase blood pressure. Angiotensin II stimulates increased thirst and ADH secretion from the pituitary to increase water reabsorption.
The ACEII receptor in the lungs allows for what?
It allows for coronavirus to be able to enter the cells of the lungs. Since those ACEII receptors are present throughout the entire body, this causes a bunch of other effects to occur as a result of COVID. (ex. GI issues)
What tells your body that you need to increase your blood pressure through the Renin-Angiotensin-Aldosterone System (RAAS?)
There are baroreceptors that determine our blood pressure at any point. These will send signals that stimulates our liver to secrete angiotensinogen. More signals come in and tell the kidneys to release renin so it can convert angiotensinogen to angiotensin I. This will go to the lungs and be converted to angiotensin II and go to the kidneys to tell them to absorb more sodium and water. Angiotensin II will get relayed to the hypothalamus such that it will tell the hypothalamus that you should be thirsty and will help release ADH. Thirst is increased to increase volume of blood and blood pressure.
Increase of sodium will lead to an increase in plasma tonicity which will stimulate ADH secretion such that this can stimulate water reabsorption to increase blood pressure.
Where is human angiotensinogen produced from and how many amino acids are the most important for this activity?
Angiotensinogen is produced by the liver (globulin protein) and only the first 12 of 453 AA are the most important. Only the first 10 AA are cleaved from angiotensinogen to convert it into angiotensin I and later on angiotensin II.
Where is renin produced and as a response to?
It’s produced in the kidneys.
- renal sympathetic activity: fight/flight response - increase blood pressure through renin which leads to production of angiotensin II and aldosterone such that heart rate goes up, such that more oxygen/nutrients are transported to muscles so you can run/fight
- decrease in blood pressure in kidneys: blood pressure too low –> renin is produced which leads to angiotensin II and aldosterone to help increase blood pressure
- decreased delivery of sodium to cells in the juxtaglomerular space: sensors are present at the cells close to the glomerulus to check sodium levels. If sodium levels drop too low, there will be signals to increase sodium absorption
Does angiotensin I have biological activity beyond being a precursor to angiotensin II?
No, its sole purpose is to be cleaved into angiotensin II
What is the role of renin? Is it a hormone?
Renin is responsible for cleaving angiotensinogen to produce angiotensin I. It’s not a hormone; rather an enzyme that mediates blood plasma volume and arterial vasoconstriction (decreases diameter of blood vessels and leads to increase of blood pressure.) It’s responsible for regulating the body’s mean arterial blood pressure.
In order to obtain renin, it has to be matured such that it goes from preprorenin –> prorenin –> renin. Why is this important for proteases?
It’s important for regulation since we don’t need them to be active 24/7. If they were active all the time, they would begin to breakdown other proteins in your body that they are not supposed to. It can tear into our muscles (ie if it’s in the stomach, we can get stomach ulcers)
Where is renin secreted? What stimulates the secretion of renin?
It’s secreted in the different arterioles of the kidney from juxtaglomerular cells in response to stimuli.
1) decrease in arterial blood pressure: low pressure activates renin release to increase blood pressure
2) decrease in sodium levels
3) sympathetic nervous system activity: fight/flight blood pressure increase through epinephrine/norepinephrine
What are the functions of ACE and where is it normally found?
ACE is a zinc metalloprotease that converts hormone angiotensin I into the active vasoconstrictor angiotensin II by removing 2 AA. It’s found in the capillaries of the lungs and endothelial and kidney epithelial cells.
Functions:
- forms vasoconstrictor angiotensin II
- increases blood pressure by degrading another protein called bradykinin - causing vasoconstriction
- degrades amyloid beta-proteins (responsible for causing Alzheimer’s) in the brain
How is angiotensin II obtained by the body? What are the roles of angiotensin II? Where does this hormone act/work?
Angiotensin II is obtained after angiotensin I is cleaved by ACE. Angiotensin II is a vasoconstrictor that acts of both smooth muscle and adrenal glands. In the smooth muscle, it raises the resistance of these arteries, putting more pressure on the heart because it will need to pump harder to be able to get blood out of the vessel. The heart will then pump harder and faster to lead to this increase in blood pressure.
In the adrenal glands, angiotensin II will lead to the production and secretion of aldosterone, leading to increase in sodium absorption and water uptake. In addition, angiotensin II acts on Na+/H+ exchangers in the proximal tubules of the kidneys to stimulate Na+ reabsorption and H+ excretion, which is usually coupled with bicarbonate reabsorption.
What degrades angiotensin II and what is the product of that? Where does this occur and why does degradation of this signal occur?
Angiotensinases, found in red blood cells and in vascular beds of most tissues, degrades angiotensin II into angiotensin III. This occurs because you don’t want angiotensin II for a long time.
How does angiotensin II stimulate the production of aldosterone?
When angiotensin II binds to some GPCR receptor in the zona glomerulosa, this will lead to the activation of Galpha-q and leads to the activation of phospholipase C. Phospholipase C breaks down PIP2 into IP3 and DAG, leading to an increase in intracellular Ca++ levels (IP3 binds to IP3 gated Ca++ channels on the endoplasmic reticulum to release Ca++, which leads to the activation of PKC. PKC leads to the phosphorylation of calcium channels and a further increase in Ca++ in the cell. G-beta/gamma proteins bind to Ca++ channels on the cell membrane to increase intracellular calcium levels. The calcium can go activate CAM kinase to phosphorylate things and leads to the production of StAR mRNA (which will get translated, go in the mitochondria, and increase cholesterol) The cholesterol becomes pregnenolone through cytochrome P450SCC and it’s used to produce aldosterone and released into the bloodstream.
When angiotensin II binds to GPCRs, this leads to an increase in intracellular calcium levels. What happens when smooth muscle cells increase levels of intracellular calcium?
When smooth muscles are flooded with calcium, this will cause the smooth muscles to contract. Smooth muscles which line arteries will contract, and as a result this will cause arterioles to narrow, leading to an increase in blood pressure.
Why might ACE inhibitors be used as antihypertensive drugs?
Angiotensin II is a strong vasoconstrictor for increasing blood pressure.
Angiotensin II stimulates smooth muscle contraction, which leads to vasoconstriction. It also leads to the production of aldosterone, which increases sodium reabsorption and water reabsorption, causing increases in blood volume and blood pressure.
By inhibiting the enzyme responsible for making angiotensin II, we prevent vasoconstriction as a result of direct angiotensin II action of smooth muscle, preventing production of aldosterone and increase in blood pressure and blood volume.
List the positive and negative regulators for aldosterone synthesis.
Positive regulators:
1) Adrenocorticotropic hormone (ACTH): leads to increase in cAMP –> production of StAR protein to allow steroid hormone biosynthesis
2) Angiotensin II: increases intracellular Ca++ and allows for production of StAR protein (allows for steroid hormone biosynthesis bc StAR allows cholesterol to be able to go into mitochondria to be able to be acted upon by cytochrome P450SCC, leading to the production of pregnenolone and aldosterone)
Negative regulators:
1) Dopamine: stops process from occurring. (dopamine issues = blood pressure issues)
Where does aldosterone act in the body, and what are the functions of aldosterone?
It acts on nuclear mineral corticoid receptors and is responsible for promoting Na+ reabsorption, water retention, and K+ excretion.
Aldosterone is able to upregulate Na+/K+ pumps. This allows for the establishment of a concentration gradient, such that more Na+ will be able to be pumped into cell and less K+ pumped into the cell.
Overall, it stimulates processes which favor Na+ and water reabsorption and K+ excretion through concentration gradient formation, upregulates channels which allow for increased permeability to Na+ and allows for reabsorption/exchange of K+ for Na+ and water in the salivary and sweat glands.
How is the renin-angiotensin-aldosterone system (RAAS) inhibited? Explain the whole process briefly.
The liver will receive signals which allows angiotensinogen to be produced and sent through the bloodstream. Renin will cleave angiotensinogen to angiotensin I and be cleaved by ACE to make angiotensin II. When blood pressure/volume has sufficiently increased, this will act as negative feedback on the kidneys to prevent renin production (and no more angiotensin I/II and aldosterone production.
What can an overactive renin-angiotensin-aldosterone system (RAAS) lead to? How can this be treated?
Overactive RAAS can lead to vasoconstriction and over-retention of sodium and water - leading to hypertension.
ACE inhibitors as well as Angiotensin II receptor blockers can be used. These are more effective than renin inhibitors and can still be used for treatment of hypertension.
What diseases are associated to issues with aldosterone? How do these diseases occur and what are their characteristics?
1) Conn’s syndrome (primary aldosteronism): results from tumors which produce excess aldosterone –> increase K+ excretion and excess renal Na+ reabsorption –> high blood pressure (treatment is to remove tumor)
2) Secondary aldosteronism: excess aldosterone can be due to dehydration, sodium depletion –> high blood pressure (treating the specific cause helps with the issues)
3) CAH type II: defect in 11beta-hydroxylase prevents development of aldosterone and cortisol –> production of androgens instead, masculinization of females, issues with salt reabsorption –> hypertension
4) Essential hypertension: unknown origin
5) Malignant hypertension: renal damage –> loss of control of renin secretion & keeps aldosterone high –> increase in blood volume/pressure
6) Addison’s Disease: adrenal glands (cortex) dying due to autoimmune response or tuberculosis. Aldosterone deficiency prevents conservation of sodium, decreased extracellular fluid, low blood pressure, weight loss, weakness
7) Liver disease: aldosterone not degraded normally –> causes excess presence of aldosterone –> increase in blood volume/pressue
