Midterm 2 Flashcards
What sets up the sodium gradient that is used to drive the secondary active cotransporters on the apical membrane of the renal tubule?
Na/K ATPase. 3 Na out through the basolateral membrane, 2 K into the epithelial cell. This is a primary active transport.
What are diuretics used to treat?
Hypertension, cardiac insufficiency (heart failure), pulmonary edema, and renal failure.
Prolines and glycines are found in the TM regions of cotransporters. What are their functions?
They work to kink these regions to form binding substrates right in the middle of the membrane. They are involved in hinging and conformational changes, very flexible.
Proximal Convoluted Tubule
60-70% of Na absorbed, 60-70% of water absorbed (follows the sodium). Leaky epithelium, permeable to water. Most diuretics act later in the tubule. Na/glucose,amino acid symport. Na/Cl symporter. Na/Proton antiporter. Na/K ATPase on basolateral membrane. Site of absorption of bicarbonate.
Osmotic Diuretics
Mannitol, similar to glucose but can’t be reabsorbed. Osmotic diuretics are filtered in the glomerulus but cannot be reabsorbed in the nephron. They reduce the passive reabsorption of water. Site of action is the proximal tubule and the descending loop of henle. Used in acute renal failure to keep fluid flowing in the nephrons, and for emergency treatment of intracranial or intraocular pressure (not kidney effects). Not useful for controlling blood pressure.
Carbonic anhydrase inhibitors
Acetazolamide. Not used as a diuretic because other mechanisms can lead to bicarbonate reabsorption downstream and they can cause a drop in pH that can cause problems. Used in the treatment of glaucoma (involves intraocular pressure). They deplete extracellular bicarbonate and can cause metabolic acidosis.
Loop of Henle
Key control of osmotic balance in the body. Ascending limb (thick part) actively reabsorbs Na. Ascending limb is poorly permeable to water, enabling an osmotic gradient. Descending limb is permeable to water but not to salts. The descending limb works passively and is a primary region for water reabsorption due to hypertonic interstitia. Countercurrent exchange mechanism: absorption of salt in the ascending limb is coupled to absorption of water in the descending limb; so the two work together.
Vasa recta
Involved in counter current exchange. Blood vessels that branch from efferent arteriole that carry reabsorbed salt and water out of the kidney. Slow blood flow prevents wash out of salts and maintains a high is molarity at the inner medulla.
Ascending limb of the loop of Henle
~25% of Na reabsorbed. Na/K/2Cl cotransporter. Low water permeability. Loop diuretics block Na/K/2Cl cotransporter by binding to the Cl site. These are the most powerful diuretics (high efficiency). Used to treat salt and water overload (cardiac insufficiency and pulmonary edema). Antihypertensives, but thiazides are preferred if there’s good renal function.
Distal Convoluted Tubule
5-10% of Na reabsorbed, Na/Cl cotransporter. Thiazides diuretics: block Na/Cl cotransporter by binding to Cl site. Less powerful than loop diuretics. Widely used as anti hypertensives and treat cardiac insufficiency. Thiazides have the ceiling effect whereas loop diuretics don’t.
Collecting duct
1-5% of Na reabsorbed. Na channel is key to Na reabsorption, electrogenic. K excretion coupled to Na reabsorption. Under hormonal control (aldosterone and vasopressin: SEE PICTURE). K sparing diuretics: Na channel blockers, competitive antagonists of aldosterone. Limited diuretic efficiency. Given with loop or thiazide diuretics to prevent K loss.
Collecting duct summary
Na flows down concentration gradient into renal epithelial cells. Na influx through Na channels causes voltage change, resulting in K efflux into tubular fluid and K loss in urine. Aldosterone promotes Na channel activation, synthesis of Na/K ATPase, Na/ proton cotransporter activation. Diuretics (Na channel blockers: amiloride, triamterene, and aldosterone competitive inhibitor spirolactone) are K sparing: Na and water are excreted in urine, K is retained in body. Vasopressin (ADH) causes insertion of aquaporins and reabsorption of water.
Bartters syndrome
Too much NaCl excretion, hypotension, neonatal presentation, more severe than gitelmans. (defective Na/K/2Cl cotransporter or K channel or Cl channel in the ascending limb of loop of henle).
Gitelmans syndrome
Too much NaCl excretion, hypotension, presentation in early adulthood, (defective Na/Cl cotransporter in the distal tubule).
Liddles syndrome
Autosomal dominant, hypertension (mutation in amiloride-sensitive Na channel resulting in more Na channels in plasma membrane than normal). Too much Na reuptake. How can it be treated?
Vasopressin
Secreted into the body and transverse the whole body, but it’s main target is the kidney. Vasopressin binds to V2 receptors located in the collecting duct which has downstream effects of inserting aquaporins into the apical membrane. This works to increase water reabsorption, thereby raising blood pressure and decreasing the amount of urine excretion in the process.
Diabetes mellitus
Too little insulin produced or cells unresponsive to insulin; excess glucose in blood causes glucose and water loss into the urine (causes renal effects but the cause is not the kidneys). Too much urine, and it is sweet.
Diabetes insipidus
Too little vasopressin produced, or collecting duct is unresponsive to vasopressin; results in excess water loss into urine. Urine is not sweet.
What are the two main types of diabetes insipidus?
Nephrogenic and neurogenic. Nephrogenic is less common and involves an inability of the kidneys to respond to vasopressin. This can be either an acquired kidney disorder or due to defective V2 receptors (nonfunctional or doesn’t appropriately traffic to the plasma membrane). Neurogenic is the most common and involves a deficiency in vasopressin production. Treated with desmopressin (a vasopressin analogue).
What are some diseases that involve protein mistrafficking?
Lysosomal diseases, cystic fibrosis, diabetes insipidus, retinitis pigmentosa, neurodegenerative diseases.
What happens to proteins that are misfolded or unassembled?
They are ubiquitinated then degraded by ERAD.
How do pharmacological chaperones work?
Give the cells a reagent that causes protein to fold correctly and more quickly and reliably. So you can give an agonist or antagonist into a functional site on the protein, which might help the protein assume it’s correct conformation because it could act as a template.
What are the criteria for identifying cotrabsporters?
Physiology: cotransporter ls require the presence if both transported substances to function. Pharmacology: are they blocked by the appropriate drugs? Anatomy: are they found in the right place?
Bumetanide
A loop diuretic.
What are the sites for blood pressure control?
Heart: decrease in force and rate of cardiac contraction. Kidney: decrease in blood volume. Blood vessels: relax vascular smooth muscle.
Treatments for hypertension and control of blood pressure.
ACE inhibitors (decrease angiotensin II). Angiotensin II receptor antagonists. Diuretics (kidney: decrease Na reabsorption, decrease blood volume). Calcium channel inhibitors (blood vessels: causes vasodilation of smooth muscle). Beta-adrenergic receptor antagonists (heart: decrease cardiac output). Alpha1-adrenergic receptor antagonists (blood vessels: block vasoconstriction by alpha1-adrenergic receptors.
What process tells the body that it needs more salt?
Juxtaglomerula cells are the sites of secretion of renin. This region of the kidney is in contact with the ascending limb of the distal tubule. Macula densa cells sense the amount of sodium and salts absorbed. Contact between the macula densa cells and the juxtaglomerula cells allows for communication to ensure renin release at appropriate times. The juxtaglomerula cells are prevalent at the afferent arteriole.
Afferent arteriole
Low blood pressure can be detected here and stimulates renin release. The area at which renin is release is innervated with sympathetic nerves.
How does angiotensin II work?
Renin release leads to several intermediates being synthesized, ultimately leading to increased angiotensin II. Angiotensin II works as a circulating hormone that interacts with the adrenal cortex. The outer region of the adrenal cortex is where aldosterone is synthesized. Angiotensin II activates a GPCR that works to stimulate aldosterone synthesis. Aldosterone is then released into the blood. Aldosterone is a steroid and works through a nuclear receptor. Aldosterone interacts with it’s receptor at the collecting duct of the kidney where it causes reabsorption of salt. Increased salt reabsorption leads to decreased urine volume and increased blood pressure.
How does renin work?
Renin is a hormone and an enzyme. Renin cleaves angiotensinogen to angiotensin I. Angiotensinogen is made in the liver but is circulating through the blood supply. Angiotensin I is not biologically active, but is converted to angiotensin II by angiotensin converting enzyme (ACE) which cleaves the 2 amino acids on the C terminal side creating angiotensin II, a very active hormone and is an 8 aa peptide. Angiotensin II can then cause aldosterone secretion.
How does aldosterone work?
Angiotensin II causes aldosterone secretion. Aldosterone goes to the collecting duct and causes salt reabsorption by increasing the synthesis of sodium channels and sodium channel mediators and sodium potassium ATPases. Angiotensin II is the most powerful vasoconstrictor and has feedback inhibition.
How does angiotensin II cause aldosterone synthesis?
Aldosterone is derived from cholesterol. The rate limiting step in aldosterone synthesis is cleavage of a side chain of the cholesterol which is catalyzed by angiotensin II. Angiotensin II also activates a number of enzymes involved in aldosterone synthesis. Angiotensin II acts directly on the blood supply to increase construction of blood vessels. Angiotensin II also increases the release of vasopressin, which also works to cause water reabsorption and increase blood pressure. So the net result is salt and water reabsorption along with an increase in blood pressure.
Actions of angiotensin II
- promotes aldosterone synthesis and release, thereby increasing sodium reabsorption in the kidney.
- direct vasoconstrictor causing increase in blood pressure.
- promoted vasopressin release from posterior pituitary, causing water reabsorption in kidney.
Captopril
And ACE inhibitor that binds to the active site of ACE. By knowing the steric restrictions of the active site, Captopril was developed. ACE inhibitors also prevent the breakdown of Bradykinin (a vasodilator) which ACE normally breaks down. Another ACE inhibitor is lisinopril.
Angiotensin II receptor antagonists
Block the effects of angiotensin II and are anti hypertensives. It’s the AT1 angiotensin II receptor that’s responsible for the blood pressure effects of angiotensin II, so inhibitors of AT1 act as anti hypertensives (Sartans e.g. Losartan).
Renin inhibitors
Block the active site of renin to prevent proteolysis of angiotensinogen to angiotensin I; are recent drugs to treat hypertension. Aliskiren
What are some general principles for G protein signaling?
- cascade of signaling molecules.
- signaling is slower than ligand-gated ion channels (but still fast) and persists longer.
- amplification of response is intrinsic to this mode if signaling.
- multiple downstream targets and multiple responses are frequently produced.
- integration and overlap of responses to different hormones/neurotransmitters.
