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| | *started here on 04/05/10. | | *started here on 04/05/10. |
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| - | ==Essential hypertensions: clues from monogenic diseases==
| + | QrnVWe I really enjoy the article post. Really Cool. |
| - | *We'll look at this as a salt and water balance issue.
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| - | *28% of the over 18 population has hypertension.
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| - | *This is becoming a major problem in this country.
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| - | *There are both environmental and genetic causes.
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| - | *Even when you factor out all the environmental issues, there are still genetic factors that predispose people.
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| - | *Thee genetic factors are complex and there are many multiple genes involved.
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| - | *We don't know what genes are involved, however.
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| - | *Though, there are some diseases that have hypertension and for these we know the gene, in some cases.
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| - | ===Statistics===
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| - | *The situation has only gotten worse in the last years.
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| - | *In the 20-34 range, only about 10% of people have hypertension.
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| - | *Over 55 in age, over 50% of people have hypertension.
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| - | *We think of hypertension as a male dominant disease, but over 55, more women are affected than men.
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| - | *Hypertension is much higher in the black population and it shows up about 10 years earlier.
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| - | *The increase from 60s to 70s correlates with increased process food and decreased exercise.
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| - | *The decrease from the 70s to 80s is from a decrease in smoking and increase in exercise.
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| - | *But now we're going back up again since 1991.
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| - | *Why do we care? Because cardiovascular disease exactly follows hypertension.
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| - | *After the age of 60, over 70 percent of the population has some form of cardiovascular disease.
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| - | *And cardiovascular disease leads to death! It is, by far, the leading cause of death.
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| - | *We spend lots of money on cardiovascular diseases.
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| - | *Quote: "We do not understand the cause of hypertension in 95% of patients, fail to achieve a normal blood pressure in 50% of patients, and are unable to fully reverse the cardiac and vascular changes that predate the diagnosis and treatments of hypertension."
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| - | **This is still valid, too.
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| - | **Ultimately, it is hard to treat a disease if we don't know what causes it.
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| - | ===Essential hypertension===
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| - | *There are two types:
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| - | **Salt senstive
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| - | ***Means that if you eat a high salt meal, your BP will go up.
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| - | ***It might be the case that once over 50 practically everyone is salt-sensitive.
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| - | **Salt insensitive
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| - | ***Means that if you eat a high salt meal, your BP will not go up.
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| - | *There is secondary hypertension, too. This comes from another cause like kidney failure or artery blockages, etc.
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| - | *We're going to talk about essential hypertension.
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| - | ===So how do you go about tracking down genes that are involved?===
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| - | *From human and mice studies, we know that hypertension seems to come from the kidney.
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| - | **We transplanted hypertensive and nonhypertensive kidneys to show this.
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| - | **We've done studies on people with human kidney transplantations, also, and confirmed this for humans.
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| - | **The hypertension tracts with the kidney, not the person.
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| - | *Salt may be a factor in forming hypertension.
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| - | ===Monogenic diseases in which blood pressure regulation is distributed===
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| - | *What in kidney contributes to hypertension?
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| - | *We're going to go over some diseases that have given us hints.
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| - | *First, Cushing and Addison are way more complicated than just hypertension.
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| - | *two more
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| - | *All of these have a component of Na resorbtion.
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| - | | + | |
| - | ====Preview====
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| - | *So, first, the renin cascade is strated.
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| - | *Aldosterone is a mineralocorticoid.
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| - | *It interacts with a mineralocorticoid receptor (which not all cells have).
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| - | *The glucocorticoids and mineralocorticoids are the two hormones that control intermediary metabolism.
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| - | What is intermediary metabolism.
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| - | *Only a few cells have mineralocorticoid receptors.
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| - | *When stimulated the mineralocorticoide receptors stimulates activation of epithelial Na transporter.
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| - | **ADH can activate it as can insulin.
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| - | *Apical: Enac allows Na to flow into cell down electrochem gradient. Basal, Na is pumped into blood.
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| - | *Apical has potassium channel which is gated by potassium such that as K goes up, K will be released into lumen.
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| - | *If you have an increase in Na in the blood and a decrease in K in the blood, the disease state will be ad the epithelial cells of the kidney.
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| - | =====Enac=====
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| - | *Responsds to amiloride (also called ?).
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| - | **Has few side effects but isn't used.
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| - | *Enac is positively regulated by:
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| - | **Aldosterone which can take hours.
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| - | **ADH which can take minutes
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| - | **Insulin which can take minutes.
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| - | *Three hormones regulating same channel in same manner.
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| - | =====Mechanisms of ENAC regulation and clinical implications=====
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| - | *Controversy over how many subunits to build channel.
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| - | *3 different domains, anyhow.
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| - | *There are very important intracellular domains.
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| - | *This channel can also be regulated by:
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| - | **positively regulated by proteolytic cleavage of extracellular domain
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| - | **negatively regulated by ubiq
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| - | **neg regulated by intracellular Na
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| - | **pos regulated by metabolic depletion of AMP
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| - | **pos / neg of phosphorylation but it isn't straightforward which way by which phos state
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| - | **pos / neg by trafficking of protein to membrane (which is how the hormones work)
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| - | *So, all the hormones work through trafficking so they are all additive in their effects.
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| - | *Over secretion of aldosterone leads to more activation of ENaC
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| - | *leads to hypertension
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| - | ====Adrenal tumors====
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| - | *These can over-secrete aldosterone which would over stimulate Enac.
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| - | *This means more Na in the blood stream which means more water and more blood volume.
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| - | *Enac seems to be the protein in the kidney that affects blood pressure.
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| - | ====Cushing disease====
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| - | *Hard to regulate the Na channel.
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| - | *Once cloned and sequenced we thought we would find mutations that explained hypertension. But we didn't.
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| - | *So it must be some regulatory unit.
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| - | *Cushings is an over production of glucocorticoids.
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| - | *This generates more than just hypertension.
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| - | **All other symptoms are explained by over production of glucocorticoids.
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| - | **Generates less muscle and more fat.
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| - | **We see diabetes because glucocortiociods are poisonous for beta cells.
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| - | *So how do increased glucocorticoids cause hypertension?
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| - | *First we'll look at aldosterone.
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| - | **It is a lipid hormone so it cross the membrane and works with intracellular receptor.
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| - | **Receptor moves to nucleus.
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| - | **There is "classic genetic derepression" which cuases increases in the channel which gets moved to the membrane.
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| - | **Not all cells have aldosterone receptor.
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| - | *Back to glucocorticoids
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| - | **They can bind the mineralocortiocid receptor just as well as aldosterone.
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| - | **Glctd are about 100X as large as aldosterone.
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| - | **How does aldosterone even bind? In cells that have mintd receptor, there is also HSD (hydroxysteroid dehydrogenase) which breaks down glctds.
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| - | *In cushings, you have so much glctds that you overwhelm HSD and they still bind the mintd receptor.
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| - | *The ENaC channel becomes constitutively active!
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| - | *This also happens in chronic administration of glctds for inflammation and such.
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| - | *Black licorice can also help to inhibit hydroxysteroid dehydrogenase.
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| - | ====Addison disease====
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| - | *Addison is the opposite of cushing: not enough glctd.
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| - | *Leads to
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| - | **Low plasma sodium (because not reabsorb)
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| - | **High plasma potassium (because not secreting)
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| - | ***Recall that high K should trigger activation of Enac, but it isn't very effective.
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| - | *These patients have low blood pressure, muscle weakness, fatigue, vomiting, loss of apetite. These mostly come from lack of glctds.
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| - | ====Apparent Minct Excess====
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| - | *Can generate extreme hypertension even in small children.
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| - | *This disease looks like an adrenal tumor that produces aldosterone excess.
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| - | *There is hypertension and hypokalemia (low K).
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| - | **These targe Enac.
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| - | **This should tell us that something is wrong with aldosterone. We'd expect it to be high aldosterone.
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| - | *But then we see that aldosterone is not high and there is low renin/angiotensin b/c the body is trying to shut down renin production.
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| - | *The spironolactone blocks aldosterone binding to the receptor.
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| - | **But aldosterone isn't low so why does this help? This tells us that the problem is probably at the aldosterone receptor.
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| - | *We also see an unusual glctd metabolite in the urine which gave us our hint:
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| - | **This comes from glctds not being broken down and we found a mutation in HSD.
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| - | *So this mutation inactivates HSD so the aldosterone receptor isn't protected from the high levels of glctds.
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| - | *We call this '''apparent minctd excess'''.
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| - | *We use amiloride and triampterene to treat. Spironolactone also works.
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| - | why?
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| - | ====Little====
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| - | *This is very rare, about 12 or 13 families worldwide.
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| - | *First diagnosed in Mississippi; large family; made it easy to do genetic studies.
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| - | *Proband came to ER with high hypertension at age 13!
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| - | **Knew there were other sibs, too.
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| - | *Within 6 months of discovering and sequencing channel, we figured out it was involved in this family.
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| - | *BP could only be controlled in the hospital.
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| - | *Characteristics:
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| - | **Increased Na and H20 retention.
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| - | **Low renin and aldosterone, just like AME.
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| - | **Decreased plasma K which says that it is likely that in the distal collecting duct it must be Enac.
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| - | **Metabolic alkalosis (think acid / base balance)
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| - | **Unlike AME, unresponsive to spironolactone. So it must be something broken after the receptor.
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| - | **Responsive to triampterene (amiloride) if she was on a low Na diet.
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| - | *So we deduced that it was the sodium channel.
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| - | **And when we sequenced their channels we found a gain of function; the channel was not being properly recycled through endocytosis.
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| - | **This mutation was on the C-terminal end of the Beta subunit.
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| - | For this portion of the test, know the different directions that K and Na travel. Know the overall figure in the book.
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| - | *Proband died of kidney failure in 30s. She got kidney transplant and it cured her hypertension.
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| - | **She now has affected children.
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| - | ====Pseudohypoaldosteronism====
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| - | *Looks like low aldosterone but it isn't.
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| - | *This is the exact opposite of Little syndrome.
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| - | *Usually diagnosed in infancy.
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| - | *Lots of Na gets secreted in urine.
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| - | **Causes low BP, dehydration, and high serum K.
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| - | *High serum K usually leads to diagnosis at birth because if we don't catch it, they die.
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| - | *Does the body try to compensate?
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| - | **Yes, high renin and high aldosterone levels.
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| - | **It is sensing the low BP, but aldosterone is doing nothing.
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| - | *We found that this was a loss of function mutation in Enac.
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| - | *Treatment:
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| - | **Supplement with Na.
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| - | **Dialyze to remove K.
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| - | **After the neonatal period, the disease is less severe because body tolerates K levels better after infancy.
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| - | *We thought that lesser mutations would be the cause of essential hypertension, but it turns out not the be the case. It must be somewhere in the pathways that control Enac.
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| | ==Metabolic syndrome== | | ==Metabolic syndrome== |
QrnVWe I really enjoy the article post. Really Cool.
