Chapter 14 - Human Physiology
Chapter 14 - Human Physiology BIOL 2213
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Chapter 14 – Renal Physiology Renal Functions – the adjective renal means “pertaining to the kidneys.” The kidneys process the plasma portion of the blood by removing substances from it and sometimes adding substances. The kidney has 5 overall functions as described below. 1. Regulation of water, ion balance, and acidbase balance – the kidneys excrete just enough water and ions to keep the amounts of these substances within a narrow homeostatic range. 2. Removal of metabolic waste – metabolic waste is excreted through the urine. Metabolic wastes include urea from the catabolism of proteins, uric acid from nucleic acids, creatine from muscle creatine, the end products of hemoglobin breakdown, and others. 3. Removal of foreign chemicals – the kidney removes drugs, pesticides, and food additives 4. Gluconeogenesis – the kidneys can synthesize glucose from amino acids and other precursors and release it into the blood. 5. Production of hormones/enzymes – the kidneys release 2 hormones, erythropoietin and 1,25dihydroxyvitamin D. Structures of the Urinary System – The kidneys are actually not located within the abdominal cavity. They are considered retroperitoneal, meaning that they are located behind the peritoneum, the lining of the abdominal cavity. Urine flows from the kidneys through the ureters into the bladder and then eliminated through the urethra. The functional unit of the kidney is the nephron. Each nephron consists of an initial filtering component called the renal corpuscle and a tubule that extends from the renal corpuscle. 1. Renal Corpuscle – Each renal corpuscle contains a mesh of capillaries called the glomerulus. Each glomerulus is supplied with blood through the afferent arteriole. The blood is taken out through the efferent arteriole. Surrounding the glomerulus is a fluid filled capsule called the Bowman’s capsule. The fluidfilled area is called the Bowman’s space. 20% of the plasma is filtered into the Bowman’s capsule. The glomerulus and Bowman’s capsule make up the renal corpuscle. Structure of the Glomerular Capillaries – There is a 3layer barrier separating blood from the Bowman’s space. First is the single celled endothelium, common to all blood vessels. Second is the basal lamina, a noncellular protein layer of the basement membrane. Third is the single celled epithelial lining of the Bowman’s capsule. The epithelial cells in the Bowman’s capsule are called podocytes, octopuslike cells in which bloodplasma fluid filters through. Podocytes are considered the visceral layer of the Bowman’s capsule and contain filtration slits. The final cell type of the glomerulus is the mesangial cells, which are modified smooth muscle cells not in direct contact with the glomerulus. Structures of the Nephron – The following structures are listed in the order of appearance in the nephron. 1. Proximal Tubule – drains the Bowman’s capsule that consists of the proximal convoluted tubule and the proximal straight tubule. 2. Loop of Henle – this is a hairpin loop consisting of the descending limb and the ascending limb. 3. Distal Convoluted Tubule – a passageway from the loop of Henle to the collecting duct. 4. Collecting Duct – this comprises of the cortical collecting duct and the medullary collecting duct. More Structure – Multiple cortical collecting ducts merge. Up until this point, all nephrons are separate from other nephrons. The cortical collecting ducts undergo multiple merging processes until they form a large medullary collecting duct which drains into the renal pelvis, the kidney’s central cavity. The renal pelvis is continuous with the ureter. There are other important regional differences in the kidney. The outer portion is called the renal cortex, which contains all the renal corpuscles. The inner portion is called the renal medulla, which contains the loops of Henle and is the site where the medullary collecting ducts pass through on their way to the renal pelvis. Capillaries of the Nephron – Besides the glomerular capillaries, other capillaries exist in the nephron. Each tubule is surrounded by peritubular capillaries. These 2 capillary sets are continuous via the efferent arteriole of the glomerular capillaries. The peritubular capillaries eventually leave the kidney through the veins. Types of Nephrons – There are 2 types of nephrons as described below. 1. Juxtamedullary – about 15% of nephrons are of this type. This means that the renal corpuscle lies in the renal cortex closest to the corticalmedullary junction. The loops of Henle go deep into the medulla. These nephron types are responsible for generating an osmotic gradient in the medulla in order for water to be reabsorbed later on in the collecting duct. In close proximity to these nephrons are the vasa recta, long capillaries that extend deep into the medulla. 2. Cortical – about 85% of nephrons are of this type. This means that the renal corpuscles are located in the outer portions of the renal cortex. The loops of Henle do not penetrate deep into the medulla. Anatomy of the Distal Tubule – the ascending loop of Henle becomes the distal convoluted tubule which passes between the afferent and efferent arterioles. At that passage point, there is a patch of cells in the wall of the ascending limb as it becomes the distal convoluted tubule called the macula densa. The outside wall of the afferent arteriole contains juxtaglomerular (JG) cells. The combination of macula densa and JG cells forms the juxtaglomerular apparatus (JGA). The JGA secretes renin into the blood. Basic Renal Processes – Glomerular filtration is the process of filtering plasma from the glomerular capillaries into the Bowman’s space. The filtrate is called glomerular filtrate. It contains no cells or proteins, but besides that contains all substances in the same concentration as the plasma. The glomeruli are great filters because of high hydrostatic pressure and large surface area. 180L of glomerular filtrate is produced per day. Proteins are retained in the capillaries to maintain osmotic pressure. Glomerular Filtration – Glomerular filtration is a bulkflow process in which water and low molecular weight substances move together. There are 2 reasons why there is no protein (albumin and globulins) in the glomerular filtrate. First, the proteins are too big to pass through. Second, the glomerular filtrate is negatively charged, just like proteins, so the proteins don’t want to be there anyways. Forces Involved in Initial Filtration – Filtration across capillaries are due to opposing Starling forces. First, hydrostatic pressure differences across the capillary wall favor filtration. Second, osmotic pressure differences because of protein concentration across the capillary wall oppose P filtration. The glomerular capillary hydrostatic pressure is denoted GC . The fluid in the P BS Bowman’s capsule exerts a hydrostatic pressure and is called . The second opposing force is the osmotic force due to different protein concentrations and is denoted as π GC . Therefore, the net glomerular filtration pressure can be described by the following relationship: NetGlomerular FiltrationPressure=P −P −πGC BS GC Rate of Glomerular Filtration – Glomerular filtration rate (GFR) is defined as the volume of fluid filtered from the glomeruli into Bowman’s space per unit time. The kidneys filter the plasma about 60 times per day. GFR is determined by: 1. Net Glomerular Filtration Pressure a. Constriction of the afferent arteriole decreases hydrostatic pressure (less incoming fluid) b. Constriction of the efferent arteriole increases hydrostatic pressure (less outgoing fluid) c. Dilation of the afferent arteriole increases hydrostatic pressure (more incoming fluid) d. Dilation of the efferent arteriole decreases hydrostatic pressure (more outgoing fluid) 2. Permeability of the Corpuscle 3. Surface Area available for Filtration – contraction of the mesangial cells reduces surface area of the glomerular capillaries which causes a decrease in GFR at any given net filtration pressure. Filtered Load – Filtered load is the measurement of the total amount of any nonprotein or non proteinbound substance filtered into the Bowman’s space by multiplying the GFR by the plasma concentration of that substance. Altering of the Filtrate – The filtrate’s composition is altered as it moves through the tubules by the movement of substances from the tubules to the peritubular capillaries and vice versa. Resorption refers to substances moving from the tubular lumen to peritubular capillary plasma. Secretion refers to substances moving from the peritubular capillary plasma to the tubular lumen. Tubular Resorption – Filtered loads are enormous and often greater than the amount of the substance that is actually in the body. Resorption of waste products is relatively incomplete. In addition, resorption of useful plasma components, such as water, inorganic ions, and organic nutrients, is relatively complete. In some cases, such as glucose, all of substance is always resorbed. The kidneys just maintain the levels that are already in the body and are outside of physiological control. In other cases, the reabsorptive rates are under physiological control for substances such as water and ions. Reabsorption does not occur by bulk flow. Two other processes are involved in reabsorption: 1. Diffusion – diffusion across the tight junctions connecting the tubular epithelial cells 2. Mediated Trasnport – requires participation of transport proteins in the plasma membranes of tubular cells Resorption by Diffusion – This is passive transport of urea out of the tubular lumen into the peritubular capillary plasma. To begin, the corpuscular membranes are freely filterable to urea, meaning that the fluid in the Bowman’s space, peritubular capillaries, and interstitial fluid are all the same. When the fluid finally begins flowing through the proximal tubule, water resorption occurs. The substances in the urea is then more concentrated than the outside. After the diffusion of water occurs, urea resorption occurs as it follows the concentration gradient. Resorption by Mediated Transport – Substances that are resorbed by mediated transport first cross the luminal membrane of the luminal epithelial cell. After substances pass through the luminal membrane, they pass through the basolateral membrane, which faces the interstitial fluid. This type of mediated transport is called Transcellular epithelial transport. Na diffuses by facilitated diffusion across the luminal membrane and is then actively pumped across the basolateral membrane into the interstitial fluid. All other substances are resorbed through coupling to sodium. The cotransported substance, like glucose or amino acids, moves uphill across its gradient by secondary active transport. Glucose then moves out of the basolateral membrane by facilitated diffusion. Transport maximum is the limit to the amounts of material that can be transported per unit time. This is because of channel saturation. When plasma glucose concentration exceeds the transport maximum for a significant number of nephrons, glucose begins appearing in the urine. Sodium Resorption – We have been talking about sodium in the filtrate so it is important to describe it further. In the blood, sodium exists in the extracellular fluid (plasma) and is therefore the ion in highest concentration in the filtrate. Resorption of sodium is active transport, although the first step is facilitated diffusion, a passive process. The active transport of the Na /K ATPase creates the electrochemical gradient needed to induce secondary active transport of glucose into the luminal epithelial cell. Tubular Secretion – Tubular secretion moves substances from the peritubular capillaries into the tubular lumen. Secretion can only occur by diffusion or mediated transport. Secreted substances must pass through 3 “doors.” The first is across the capillary wall. The second is across the basolateral membrane. The third is across the luminal membrane. Active transport must be present at least one of these “doors,” in which the secreted substance is often coupled to the resorption of sodium, as described earlier. Tubular secretion is the mechanism responsible for controlling blood pH. Tubular Metabolism – The tubules can undergo gluconeogenesis, a process of creating glucose from substances, including amino acids. Because of this, during fasting, the cells of the renal tubules can synthesize glucose to be absorbed by the peritubular capillaries. Regulation of Membrane Channels and Transporters – Tubular resorption and secretion are under physiological control. This control is achieved by regulating the concentrations of transport and channel proteins. This regulation is achieved by hormones and paracrine or autocrine factors. Division of Labor in the Tubules – GFR (glomerular filtration rate) must always be very high. The primary role of the proximal tubule is to reabsorb most of the filtered water and solutes. The proximal tubule also secretes solutes, except K . The primary role of the loop of Henle is to resorb large quantities of ions. The distal segments are responsible for fine tuning the concentrations of solutes in the filtrate, by adjusting their rates of resorption and secretion. Most homeostatic controls act upon the most distal segments of the tubule. Micturition – Urine is created and finetuned in the tubules and collects the renal pelvis. Urine then travels down the ureters into the bladder. The ejection of urine from the bladder is called micturition. The smooth muscles of the bladder are collectively called the detrusor muscle. The base of the bladder forms a neck, in which the urethra begins its function. This bladderurethra junction contains the internal urethral sphincter. Just below the internal urethral sphincter is the external urethral sphincter, which is a ring of skeletal muscle. The contraction of the external urethral sphincter can prevent urination. Innervation of the Bladder – The bladder is innervated by the parasympathetic nervous system while the sphincters are innervated by the sympathetic nervous system. 1. Bladder at Rest – There is weak parasympathetic stimulation so the bladder is relaxed. There is strong sympathetic stimulation to the sphincters so the sphincters are contracted and closed. 2. Bladder in Motion – There is strong parasympathetic stimulation so the bladder is contracted. There is weak sympathetic stimulation to the sphincters to the sphincters are relaxed and open. TotalBody Balance of Sodium and Water – There are 2 sources of body water gain. Water can either be produced from the oxidation of organic nutrients or from water intake through liquids and foods. Water can be lost in 4 ways: skin, respiratory airways, gastrointestinal tract, and the urinary tract. The loss of water from the skin is called insensible water loss. Basic Renal Processes for Sodium and Water – Water and sodium both filter into the Bowman’s space. They both undergo considerable reabsorption, but no secretion. There are 2 assumptions needed before we continue: 1. Sodium resorption is an active process occurring in all tubular segments. 2. Water resorption is by osmosis and is dependent on sodium reabsorption (water follows the sodium to maintain concentration balance). Primary Active Sodium Resorption – Sodium first moves downhill across the luminal membrane + + of the luminal epithelial cells. The sodium moves by primary actives transport (Na /K ATPase) out of the cell via the basolateral membrane into the interstitial fluid. Sodium moves into the cell with a coupled reaction. Either glucose is moved by cotransport into the epithelial cells or hydrogen ions are moved by Countertransport from the epithelial cell into the lumen. Coupling of Water Resorption – As ions (including sodium) are resorbed, water is resorbed by osmosis. Most water is resorbed by the proximal tubules. There are 4 steps in water resorption in the proximal tubules. 1. Sodium is transported from the lumen to the interstitial fluid. 2. Water concentration is high in the lumen and low in the interstitial fluid. 3. Water moves from the lumen to the interstitial fluid through water channels called aquaporins. 4. Water and sodium are moved by bulk flow into the peritubular capillaries. Water Resorption in the Collecting Ducts – In the proximal tubules, water resorption is an automatic process that is not under physiological control. However, water resorption in the cortical and medullary collecting ducts is under physiological control and can vary greatly. The major determinant of this controlled permeability is vasopressin (antidiuretic hormone or ADH). ADH is a peptide hormone secreted by the posterior pituitary gland. ADH stimulates the insertion of specific aquaporins into the luminal membrane. Therefore, aquaporins are absent in the collecting ducts unless ADH is present. Urine Concentration: The Countercurrent Multiplier System – Highly concentrated urine is called hyperosmotic, meaning its osmolarity is high (low water) and is a result of ADH. The osmolarity of plasma is between 285 and 300 mOsmol/L. Urine can be as concentrated as 1400 mOsmol/L. The major way in which this is achieved is called the countercurrent multiplier system, which is created from the opposing flow in the two limbs of the loop of Henle. Countercurrent Multiplier System In the proximal tubule, sodium and water are reabsorbed in the same proportion, so the filtrate entering the descending loop of Henle has the same osmolarity as plasma. The ascending limb is impermeable to water but actively resorbs sodium and chloride through cotransport. The net result is a hyperosmotic solution (increased solutes) in the interstitial fluid of the medulla. The descending limb of the loop of Henle is highly permeable to water but not to solutes. Therefore, water diffuses out of the descending loop to maintain osmolarity. However, equal osmolarity is never actually obtained because the ascending loop constantly pumps sodium chloride out to maintain interstitial fluid that is always hyperosmotic. Because of this, the medulla is always hyperosmotic, which causes the collecting ducts to diffuse water out of the system and concentrate urine. Concentration of Urine – Urine is normally dilute because of the active resorption of sodium chloride out of the ascending loop of Henle and distal convoluted tubule. If there is a lot of water in the body system, the kidney just leaves the filtrate alone at this point. If the body needs to conserve water, ADH is secreted into the system so that water is reabsorbed by the body from the collecting ducts. ADH allows for water to diffuse. Urine concentration can be as low as 70 mOsm/L to as high as 1200 mOsm/L. Glomerular Filtration Rate – GFR is the glomerular filtration rate and is defined as the volume of filtrate formed each minute. GFR can be affected by the following things: 1. GFR is reduced when there is a reduced net glomerular filtration pressure. This occurs in response to lowered arteriole pressure and specific reflexes acting on the renal arterioles. The reflex is a baroreceptor response, as described in chapter 12. A decrease in cardiovascular pressure causes neutrally mediated vasoconstriction. 2. GFR is increased by neuroendocrine inputs. When sodium levels increase, the overall plasma volume increases. Plasma volume increases GFR that results in a greater Na loss in the kidneys. In other terms, sodium increases blood volume, which increases blood pressure, which increases GFR. Glomerular Filtration Rate – The control of GFR can be visualized by the following mechanism: Sodium Regulation – The control of sodium in the body is mostly affected by sodium resorption, not GFR. The major factor affecting the resorption of sodium is the hormone, aldosterone. Aldosterone – Aldosterone is a steroid hormone produced in the adrenal cortex. It is a slow acting hormone that affects gene expression for the protein pumps found in the distal convoluted tubule and cortical collecting ducts. By the same mechanism, aldosterone also stimulates sodium resorption by the large intestine and the sweat and salivary glands. Therefore, the goal of aldosterone is to maintain sodium in the body through reabsorption. 1. Finally, most sodium in the filtrate of the tubules is reabsorbed anyways. When aldosterone is not present, 2% of the sodium is not reabsorbed, but secreted. When aldosterone is present, almost all of the sodium is reabsorbed by the body. When a person eats a highsodium diet, aldosterone levels are low. ReninAngiotensin System – Renin is an enzyme secreted by the juxtaglomerular cells in the kidneys. Once in the bloodstream, renin splits angiotensinogen into a small polypeptide called angiotensin I. Angiotensin I undergoes cleavage to become angiotensin II. The conversion of angiotensin I to angiotensin II is achieved by the enzyme, angiotensinconverting enzyme (ACE). ACE is found primarily on the luminal surface of capillary endothelial cells. This way, when the juxtaglomerular cells produce renin, angiotensinogen can be quickly converted to angiotensin II. Angiotensin II stimulates the secretion of aldosterone and the constriction of arterioles (increasing GFR). Angiotensin II – Angiotensin II is high during salt depletion, because angiotensin II yields aldosterone, which causes sodium resorption. When there is low sodium, angiotensin II is produced to increase aldosterone. On the other hand, angiotensin II is low when salt intake is high, because angiotensin II yields aldosterone, which causes sodium resorption. When there is high sodium, angiotensin II is not produced so that sodium can be secreted. Control of Renin – What are the mechanisms by which sodium depletion cause an increase in renin secretion? 1. Renal Sympathetic Nerves – Low sodium creates low blood volume and low blood pressure, so sympathetic nerves are activated that cause vasoconstriction, raising blood pressure and directly innervating juxtaglomerular cells. 2. Intrarenal Baroreceptors – The juxtaglomerular cells are baroreceptors themselves, and when blood pressure lowers, they are stretched less, causing them to produce more renin. 3. Macula Densa – The macula densa senses the sodium concentration in the tubular fluid flowing past it. A decreases salt concentration causes the release of paracrine factors that diffuse from the macula densa to the JG cells, causing them to release renin. Atrial Natriuretic Peptide – This is called ANP or ANF or ANH. Cells in the cardiac atria secrete ANP. ANP inhibits tubular resorption of proteins. It also acts on the renal blood vessels to increase GFR, further increasing sodium excretion. Finally, ANP directly inhibits aldosterone secretion, so that sodium cannot be absorbed as much. ANP is produced when there is an excess of sodium in the body. Renal Water Regulation – Water excretion is the difference between GFR and resorbed water volume. The rate of water resorption from the tubules is the most important factor in determining how much water is excreted. Vasopressin is the hormone in control of water excretion. Osmoreceptor Control of Vasopressin Secretion – Sometimes, water and sodium cannot be regulated with the same mechanism so there needs to be a way of regulating water excretion without altering sodium excretion. Water intake does not alter extracellular volume as much as sodium does (because sodium stays on the outside of the cell while water is mainly on the inside of the cell). However, there is a major change in the osmolarity of the body fluids. Osmoreceptors in the hypothalamus sense changes in osmolarity and control vasopressin secretion. When water is ingested, body fluid osmolarity is lowered, resulting in reduced vasopressin secretion via hypothalamic osmoreceptors. Therefore, water permeability of the collecting ducts is reduced, and hypoosmotic (a lot of water; dilute) urine is excreted. In other words, increased vasopressin increases water resorption. In conclusion, when osmoreceptors detect low osmolarity (high water), vasopressin is decreased. Baroreceptor Control of Vasopressin Secretion – A decreased extracellular volume due to diarrhea or hemorrhage yields increased action of the reninangiotensin system, increasing aldosterone, so that sodium resorption increases and adequate body water volume is maintained. In addition, a decreased extracellular volume also triggers an increase in vasopressin secretion. The vasopressin increases water permeability of the collecting ducts, increasing resorption and decreasing excretion. This is initiated by baroreceptors in the cardiovascular system. When pressure decreases due to decreased extracellular fluid, baroreceptors reduce their firing rate. Reduced baroreceptor firing increases vasopressin secretion. In conclusion, when baroreceptors detect low blood pressure (low water), vasopressin is increased.