ADH, Water Excretion, Renin-Angiotensin System (PDF)

WSUSOM Medical Physiology Rossi-Renal Physiology Page 1 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system Antidiuretic hormone, water excretion, renin-angiotensin system Learning Objectives: 1. Distal tubule and collecting duct (with part...

WSUSOM Medical Physiology Rossi-Renal Physiology Page 1 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system Antidiuretic hormone, water excretion, renin-angiotensin system Learning Objectives: 1. Distal tubule and collecting duct (with particular attention to water handling) A. Understand the role of vasopressin (antidiuretic hormone) in urinary concentration 1) Learn the source, location, and characteristics of vasopressin 2) Understand the osmotic and non-osmotic forces that influence the release of vasopressin and how they do so 3) Understand the cellular mechanisms induced by vasopressin in the principal cell to alter urinary concentration 4) Learn the role of specific water channels, particularly aquaporin 2, in tubular water reabsorption B. Identify the principal cell and its role and components involved in urinary concentration and dilution C. Be able to explain how the collecting duct works in concert with the medullary gradient established by the loop of Henle to provide either a dilute or concentrated urine D. Learn the range of urinary osmolalities that are physiologically possible in adult humans 2. Juxtaglomerular apparatus and renin-angiotensin-aldosterone system A. Describe the components of the juxtaglomerular apparatus, its anatomic location and the function of its components B. Identify the components of the renin-angiotensin-aldosterone system, know the location of each component, the enzymes or factors required in each segment of the cascade and where they are located, and have a clear understanding of the role of each of the major components on renal handling of sodium and water (e.g., angiotensin II, aldosterone, etc.) C. Learn the major factors that stimulate or inhibit renin secretion by the kidney 3. Be able synthesize the responses to ADH, Ang II, and other neurohormones into a concerted renal response to volume and blood pressure challenges like hemorrhage WSUSOM Medical Physiology Rossi-Renal Physiology Page 2 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system Vasopressin = Antidiuretic Hormone AVP = ADH peptide synthesized in magnocellular neurons of hypothalamus (SON = supraoptic nucleus and PVN= paraventricular nucleus) axons terminate in posterior pituitary released by neurosecretion release controlled by osmolality, pressure/volume, neurotransmitters ADH, antidiuretic hormone, is also known as vasopressin. You will also find it abbreviated AVP, for arginine vasopressin. Plasma Osmolality If water evaporates, solute remains behind…the number of solute particles per water increases = higher osmolality. The same thing happens to a person who is dehydrated (loss of water without loss of commensurate solute), his/her plasma osmolality will increase. Thus, a change in osmolality reflects a change in water balance for a given number of particles. When water content goes DOWN, plasma osmolality goes UP then ADH goes UP When water content goes UP, plasma osmolality goes DOWN then ADH goes DOWN. Stimuli for Secretion of ADH - Baroreceptors The arterial (high pressure) and venous (atrial; low pressure) baroreceptors sense pressure (stretch). Under normal circumstances the baroreceptors tend to keep a brake on vasopressin secretion. That is, vasopressin secretion is tonically inhibited at normal pressures. Nerve endings in the large arteries (aorta and carotid, high pressure areas) and in the atria (low pressure areas) sense pressure (actually sense stretch). Greater stretch results in the nerves sending inhibitory inputs to the brainstem and thence to the hypothalamus. Decreased stretch (low blood pressure or low blood volume) stops the inhibition, which is another way to say that the brake is off and permits ADH to be released. When blood pressure OR blood volume goes UP, vasopressin (ADH) goes DOWN. When blood pressure OR blood volume goes DOWN, vasopressin (ADH) goes UP. WSUSOM Medical Physiology Rossi-Renal Physiology Page 3 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system Osmolality regulates vasopressin separately from the baroreceptors, but they can interact. (We discuss this more next year). The three major factors controlling ADH secretion (recap): 1. Osmolality - during dehydrated conditions when there is true loss of water in excess of the loss of solute, the osmolality of body fluid compartments increases. This rise in osmolality is sensed by the specialized area of the brain (osmoreceptors which lie outside the blood brain barrier). ADH is secreted from the neural lobe, and acts on the collecting duct to increase permeability to H2O and prevent H2O loss in the urine as much as possible. Likewise, ingestion of water/hypotonic fluids will decrease osmolality. When the osmoreceptors sense the decreased osmolality, ADH release is turned off. 2. Arterial (high pressure) Baroreceptors - sensors within the carotid and aortic arch sense stretch induced by changes in blood pressure. If pressure increases, stretch increases and impulses through the 9th and 10th cranial nerves inhibit ADH. The opposite happens when blood pressure is low. 3. Volume (low pressure) receptors - sensors in the left and right atria sense stretch depending on the filling of the atria. When the atria are not filled as in hemorrhage, the stretch decreases, nerve impulses decrease and ADH increases. Note that increased nerve activity decreases ADH and decreased nerve activity increases ADH. Problem: In hemorrhage when both volume and pressure decrease, what would you expect ADH to do? Osmotic release of ADH Normal plasma osmolality for a human is about 285 ± 5 mosm/kgH2O. Note that there is a progressive increase in ADH as soon as plasma osmolality increases about 1% above this normal value (threshold for ADH). In contrast, when pressure OR volume decrease it takes a substantial change (about 10% at least, sometimes 20% depending on the speed of the change) for the baroreceptor (non-osmotic) stimulation of ADH to occur. But, once the baroreceptor associated release of ADH does occur, the rate of ADH rise is very steep. WSUSOM Medical Physiology Rossi-Renal Physiology Page 4 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system Summary of Stimuli for Secretion of ADH Increased plasma osmolality (osmoreceptor neurons) Water deficit ® ­ Posm ® ­ ADH secretion ® ­ Uosm ¯ V Water excess ® ¯ Posm ® ¯ ADH secretion ® ¯ Uosm ­ V Arterial pressure (baro) receptors in aortic arch & carotid sinus ­ pressure ® ­ stretch ® ­ afferent nerve activity ® ¯ ADH ¯ pressure ® ¯ stretch ® ¯ afferent nerve activity ® ­ ADH Volume receptors (also “baro” but low pressure) in atria ­ volume ® ­ stretch ® ­ afferent nerve activity ® ¯ ADH ¯ volume ® ¯ stretch ® ¯ afferent nerve activity ® ­ ADH Other (Non-osmotic, Non-baro) Stimuli for Secretion of ADH Hormones, neurotransmitters, drugs Angiotensin II - stimulates thirst and ADH Nicotine - stimulates ADH Ethanol - inhibits ADH Catecholamines, endothelin, prostaglandins, dopamine, nitric oxide, serotonin, cannabanoids, etc. etc. – stimulate ADH Chemo and other receptors Hypoxia, low pO2 – stimulates ADH Hypercarbia, high pCO2 - stimulates ADH Cold - inhibits ADH These are just a few of the substances that act within the brain to influence ADH. Some inhibit, some stimulate. More next year... Problem: Think about the mechanism why individuals may feel the urge to urinate when they are in a pool of fresh water? Clinical note: Ecstasy (3,4-methylenedioxymethamphetamine) acts on 5HT2 serotonin receptors, causes ADH release and simultaneously stimulates intense thirst. This leads to “water intoxication” and brain edema and death reported at rave events. WSUSOM Medical Physiology Rossi-Renal Physiology Page 5 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system ADH Action in the Kidney H2 600 O H2 1200 O H2O >1200 Recall the hypertonic medullary interstitium and how it works in concert with the collecting duct. Cellular Mechanism of ADH Actions on Kidney Principal Cells 1. ADH secreted into the plasma acts upon V2 (vasopressin) receptors on the basolateral membrane of the principal cells in the collecting tubules and ducts. 2. Activation of V2 receptors elicits a cascade of intracellular events: activation of adenyl cyclase to form cAMP which, in turn, activates protein kinase A. Protein kinase A (PKA) phosphorylates aquaporin 2 (AQP2). This culminates in insertion of AQP2 water channels into the apical membrane. 3. The basolateral membrane has AQP 3 and AQP4. 4. When AQP2 is in the apical membrane, H2O can enter the cell and then leave via AQP3 and AQP 4 into the ISF and then enter the plasma compartment in the ascending vasa recta. 5. H2O is resorbed via these channels to come into osmotic equilibrium with the corticomedullary gradient, thus the osmolality of the TF rises and the final urine becomes concentrated. 6. When ADH decreases, some AQP2 channels are sloughed out into the urine and others are recycled out the apical membrane into vesicles in the cytoplasm for reinsertion at a later time. Thus, the apical membrane becomes impermeable to H2O again and the TF can remain dilute. WSUSOM Medical Physiology Rossi-Renal Physiology Page 6 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system Diabetes Insipidus These individuals have copious urine flow rates (12-28 L/day) with low urine osmolality and are particularly prone to dehydration. Diabetes insipidus can be hereditary or acquired. Diabetes insipidus can be central or nephrogenic Neurogenic or central diabetes insipidus = lack of ADH secretion Nephrogenic diabetes insipidus o Mutation of ADH receptors (V2 receptor) in collecting duct o Mutation of aquaporin 2 (AQP2 channel) in collecting duct Question A 32 year-old woman finishes running a marathon. She drinks 6 L of water in an attempt to replace the fluid she lost during the race. Drinking excessive water after prolonged strenuous exercise causes which of the following? A. decreased urine osmolality B. increased hormonal secretion from the posterior pituitary C. increased plasma osmolality D. increases in aquaporin transport in the collecting duct E. stimulation of osmo-receptors in the hypothalamus Clinical-physiological explanation: It is important to know that drinking too much water too fast, even if someone is dehydrated can lead to brain edema. The kidney can excrete a LOT of water but it still takes TIME. The rate of excretion of water maximally is about 0.5 – 1 L/hr. Water can equilibrate across cell membrane very quickly, including brain cells. If a person drinks water too quickly before solutes can equilibrate or the kidney can excrete any excess water, then the brain can swell excessively and herniate through the foramen magnum. This leads to very rapid death. Several years ago, 6 women and 1 man died after running a marathon and drinking too much water too fast. Others have died as well in other races due to this. (Up to 13% of runners in the Boston Marathon developed low plasma osmolality during the run. NEJM 352:1150, 2005). The American Sports Association changed its recommendations regarding fluid intake in races because of these deaths. WSUSOM Medical Physiology Rossi-Renal Physiology Page 7 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system Renin-Angiotensin-Aldosterone System Juxtaglomerular Apparatus Macula densa cells of the distal tubule sense delivery of [NaCl] in the TF to this portion of the nephron Extraglomerular mesangial cells (EGM) transduce signals (prostaglandin, adenosine) Granular cells of the afferent arteriole specialized vascular smooth muscle cells (VSMC) make and secrete renin As the thick ascending limb emerges from the medulla, the distal tubule passes between the afferent and efferent arterioles. The cells of this tubule segment are specialized and have no basement membrane separate then from the extra-glomerular mesangial cells. By a series of steps, information about the amount of NaCl in the TF is transmitted back to the afferent and efferent arterioles and to the specialized granular cells of the afferent arteriole that secrete renin. E.g., ¯ NaCl in TF at macula densa → ¯NaK2Cl reabsorption by macula densa cells → ↑ prostaglandin E2 by EGM cells → ↑ renin secretion by granular cells Do not confuse this with tubuloglomerular feedback (TGF) which happens at the same place and uses signaling by the same cells. These cells are great at multi-tasking! *** Decreased NaCl delivery causes INCREASED renin secretion and afferent arteriolar DILATION (TGF). The histological figure shows the granular cells staining for renin (lower left corner). Note how few the number of cells there really are in the NORMAL glomerulus. In pathological states, the number of cells expressing renin can increase dramatically. Note the relationship of the macula densa cells with the juxtaglomerular cells and the extraglomerular mesangial cells. There is no basement membrane between the macula densa and the juxtaglomerular cells, so they can easily talk to each other with autocrine substances. Also note the presence of sympathetic nerves (see figure next page). WSUSOM Medical Physiology Rossi-Renal Physiology Page 8 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system Three major factors regulating renin secretion: 1. Perfusion pressure: Stretch of the JG cells - Decreases in pressure ® ↓ stretch of JG ® ↓ [Ca2+]i ® increases renin - Increases in pressure ® ↑ stretch of JG ® ↑ [Ca2+]i↑ ® decreases renin (Note that the response to in intracellular Ca2+ is paradoxical.) 2. Sympathetic nerve activity - Increases in sympathetic nerve activity ® activation of b receptors on JG cells ® increases renin secretion - Decreases in sympathetic nerve activity ® less activation of b receptors on JG ® decreases renin secretion - Increased plasma catecholamines (norepinephrine and epinephrine from adrenal gland) ® activation of b adrenergic receptors on JG ® increase renin 3. NaCl load (delivery) at the macula densa (NaCl load = [NaCl]tubule * TF flow rate - Reduced systemic blood pressure ® reduced GFR ® reduced filtered load of NaCl ® reduced delivery of NaCl to MD cells ® increase renin secretion - Increased systemic BP ® increased filtered load of NaCl ® increased delivery of NaCl to MD cells ® decrease renin secretion Renin-Ang II-Aldosterone System Renin is rate limiting for the cascade Catalyzes angiotensinogen to Ang I Angiotensin II Formed from Ang I by angiotensin converting enzyme I (ACE I) constricts vascular smooth muscle Increases Na reabsorption by PCT stimulates aldosterone secretion stimulates ADH secretion and thirst by direct action on brain sites Aldosterone stimulates Na reabsorption by principal cells of the collecting tubules and duct WSUSOM Medical Physiology Rossi-Renal Physiology Page 9 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system 1. Renin is secreted into the circulation by the granular cells (also known as JG cells). 2. Renin then acts on angiotensinogen made in the liver to form angiotensin I. 3. Angiotensin I is carried to the lung where angiotensin converting enzyme (ACE) removes one amino acid from angiotensin I converting it to angiotensin II. Angiotensin II acts through its receptor, AT1. Some of its most important functions are 1. Vasoconstriction – thereby increasing vascular resistance and increasing BP. 2. Stimulation of release of mineralocorticoid hormone, aldosterone, from the adrenal gland 3. Increases Na reabsorption by the proximal tubule (also the distal tubule) 4. Acts on brain areas outside blood brain barrier to increase thirst and ADH secretion (Note: there are other angiotensins from further breakdown by peptidases. Their functions are complex and secondary to that of angiotensin II) Consider Hemorrhagic SHOCK: BIG decrease in stretch in blood vessels Now you are NOT in the autoregulation range…you are in trouble 1. Neurohormonal response to hypotension at the JG cell increased plasma renin directly increased sympathetic nerve activity, thus indirectly, increases renin increased plasma catecholamines from adrenals thus indirectly, increases renin 2. Neurohormonal response to cardiac/carotid baroreceptors increased ADH secretion (by decreasing afferent nerve inhibition) decreased atrial natriuretic hormone directly by decreased stretch of atrial sensors 3. As a result of these neurohormonal responses… vasoconstriction due to Ang II and sympathetic nerve actions (this would oppose the direct myogenic response) increased thirst and water intake (if possible) in response to Ang II decreased GFR (remember now we are out of the autoregulatory range!) increased reabsorption of Na by the tubules in response to Ang II and aldosterone (next lecture) decreased Na excretion decreased water excretion in response to ADH WSUSOM Medical Physiology Rossi-Renal Physiology Page 10 of 10 Antidiuretic hormone, water excretion, renin-angiotensin system A decrease in blood pressure and/or extracellular fluid volume (ECV) will activate a number of mechanisms. Each of the mechanisms listed above are designed independently to increase the blood pressure and to restore the blood volume: - Vasoconstriction (systemically) increases blood pressure directly. Vasoconstriction in the kidney (afferent arteriole) would counteract the myogenic response tendency to vasodilate. - A decrease in GFR permits less fluid to be filtered, hence potentially lost. - Norepinephrine and Ang II increase Na reabsorption by proximal tubules. - ADH increases the reabsorption of water distally. - Aldosterone enhances Na reabsorption by the distal tubules and collecting ducts. - Atrial natriuretic hormone (ANH) decreases proximal and distal Na reabsorption, but since ANH decreases, these losses are prevented as well. All in all, the kidney is primed to excrete the lowest amount of Na possible when volume and blood pressure are threatened, thereby defending ECF volume and blood pressure. Supplement for the time of COVID-19- not on exam or STEP 1 A more sophisticated view of Angiotensin signaling (and this is “simplified”) ACE2 is a separate enzyme from ACE that we usually talk about. ACE2 converts Ang II to Ang (1-7) and Ang I to Ang (1-9) that then can be converted to Ang (1-7). Ang II via AT1 receptors leads to vasoconstriction, fibrosis, inflammation, thrombosis, pulmonary damage and abnormal pulmonary vessel permeability. Ang (1-7) stimulates AT2 and Mas receptors that lead to vasodilation and decreased fibrosis, inflammation, thrombosis and pulmonary damage. ACE2 is an enzyme BUT it acts as a RECEPTOR for the Sars-CoV2. The protease TMPRSS2 acts then to permit viral entry into the cell. Curran, Frontiers in Pharm 2020