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If If one gives an agent to minced muscle tissue that inhibits the enzyme that converts intermediate D to intermediate E in the biochemical pathway below, which which is the first intermediate whose concentration concentration will increase? A→B→C→D→E A) A B) B C) C D) D E) E Where Are We?
I have discussed:
– How nutrients and oxygen enter our blood, how the blood circulates throughout the body to bring nutrients and oxygen to each cell, and and how cells use the nutrients and oxygen to to make ATP that is used for energy and biosynthesis. Today I will discuss:
– How the kidneys filter the blood, regulate the hydration of the body and produce a hormone that stimulates red blood cell formation in bone marrow. The Internal Milieu
According to Claude Bernard, each cell is free to live live and respire in the the body because it is surrounded by an internal internal milieu that is in equilibrium with the blood. In In His Own Words…
"The living body, though it has need need of the surrounding environment, is nevertheless relatively relatively independent of it. This independence which the organism has of its external environment, derives from the th fact fact that in the living being, the tissues are in fact withdrawn withdrawn from direct external influences and are protected protected by a veritable internal environment which is constituted, in particular, by the fluids fluids circulating in the body." Keeping the Internal Milieu Constant
The internal milieu or internal or interstitial interstitial fluid is regulated is by the exchange of solutes with the blood in the capillaries. The small intestine small replenishes replenishes the nutrients necessary necessary for cellular respiration, biosynthesis and work that have been depleted from the blood and interstitial fluid. The lungs keep the keep oxygen/carbon oxygen/carbon dioxide composition of the blood and interstitial fluid constant. Keeping the Internal Milieu Constant ↑ Interstitial Fluid The kidneys (as well as the endocrine glands I kidneys will will discuss next time) help keep everything else else (e.g. water, acidity, osmolarity, Na+, water, osmolarity, K+, and glucose) in the interstitial fluid and blood plasma constant. constant. The kidneys The kidneys perform their function by filtering filtering the blood, re-absorbing the renecessary components from the urinary duct back to the blood, secreting wastes from the secreting blood into the urinary duct, and excreting the excreting the wastes as urine. 1 We Are What We Don’t Excrete
According to Homer W. Smith, “in the last analysis, composition of the the plasma is determined not not by what the body ingests but by what the kidneys retain and what they excrete.”
From Fish to Philosopher Man and His Gods Camels Have to Be Good at Conserving Water to Maintain a Hydrated Internal Milieu
Homer W. Smith came to this conclusion in part from following circus camels while he was holding a pot so that that he could collect their urine in order to understand how these desert animals could excrete such concentrated urine and such little water. Structure of Kidney The Kidney’s Blood Supply
Blood enters the kidney through arterioles that branch off from the renal artery. The renal artery enal branches branches off from the aorta. aorta The blood returns to the body through renal venules that lead to renal veins that lead to the vena vena cava. The renal arteriole elaborates into a net-like netstructure known as the glomerulus. glomerulus The The blood passing through the glomerulus is glomerulus under pressure. The pressure forces some of the fluid and solutes (excluding cells and proteins) out of the blood and into a tubule whose “opening” surrounds the glomerulus and is known as Bowman’s capsule. Bowman’s 2 The Filtrate
The filtrate passes into the proximal proximal convoluted tubule, the loop of Henle loop and the distal convoluted convoluted tubule before it passes into the collecting duct, collecting through through the ureter and into the bladder bladder and urethra, from urethra which it is excreted. excreted The Blood
The blood that does not pass out of the glomerulus continues through the renal arteriole and capillaries from from which additional wastes are secreted secreted into into the tubule and valuable constituents are re-absorbed into reinto the capillaries that capillaries that will eventually empty into the renal vein. The Nephron
The functioning unit of the kidney, which includes the tubule and the associated blood vessels is known as the nephron nephron. Each Each kidney contains approximately 1 million nephrons that make up about 176 miles (80 176 km) of tubules that function in the cleansing and homeostatic regulation of the blood. The Function of the Kidneys
Remove nitrogenous wastes (urea) that result from the breakdown of amino acids and nucleic acids Maintain the correct balance of glucose, salts (e.g. Na+ and K+) and water in the blood. Maintain the correct osmolarity so that cells do not shrink or lyse. Maintain the correct blood pH (H+ and HCO3-). and Maintain Maintain the correct blood volume and pressure. Secrete Secrete a hormone (EPO) that causes the bone marrow to synthesize red blood cells. The Formation of Urea
The breakdown (deamination) of amino acids in the liver liver results in the formation of ammonia. ammonia Ammonia Ammonia is toxic and is converted converted in a cyclic cyclic reaction reaction in the liver to the less toxic urea. less urea The urea is filtered out of the blood by the kidneys kidneys and is excreted in the urine. urine The Urea Cycle of the Liver 3 The Urea Cycle was Hans Krebs’ First Cycle More Than 1000 Liters Blood /Day Pass Through the Kidneys
The kidneys receive about 20-25% of 20the arterial blood that comes from the heart. If If the volume of blood pumped by the the heart is 75 ml/beat and the heart beats 70 beats/minute, then the heart pumps 7560 liters/day. If 22% of that blood goes to the kidneys to be filtered, then the kidneys pass about 1663 liters/day. The Numbers
>1000 liters blood/day flow into the kidneys. Approximately 200 200 liters of fluid/day pass th bl out of the blood and into the the tubules. Luckily, about 198 198 liters of fluid/day is reabsorbed by the blood stream and we only eliminate about 2 liters liters a day as urine. The Inside of Thomas Jefferson’s Outhouse How How do we figure out how any organ (e.g. the kidney) works?
According to Ernest Starling, “there are “there two main avenues of approach in the th attempt attempt to unravel the complicated processes which determine the function of any individual organ.” Two Approaches “…we “…we may study its reaction in the intact intact animal to comparatively small environmental changes— changes—a method of inestimable value, since it is one which may readily be applied to man” “…we may remove the organ and study its remove reaction under grossly artificial conditions.” 4 Every Technique Has Merits and Demerits
“In the former case, we sacrifice simplicity and full control to a close approximation to normality normality in environment; environment; in the latter case, we sacrifice normality in environment in order to obtain greater simplicity and a higher degree of experimental control.” Every Technique Has Merits and Demerits
When isolating organs, “…we attempt to dissociate the medley of influences which share in determining the normal function of the organ, and to relegate to of and each each its particular office in maintaining this normality…we attempt to associate these influences…in such a manner as to bring the isolated organ back to an environment and function comparable to the normal.” Picasso’s (1913) Woman in an Armchair
• How do you keep an isolated kidney “alive”?
An isolated organ needs plenty of oxygen oxygen for the oxidation of glucose. An An isolated organ needs plenty of chemical energy in the form of glucose, not only to glucose pe perform its function, but to maintain the but to cells and their membranes that perform the functions. Depending on how long an organ is isolated, it may need, in part, vitamins vitamins necessary to make the cofactors required for the burning of glucose, the amino amino acids required to make enzymes and the lipids lipids necessary to make the membranes. Attempts in Obtaining Isolated and Functional Kidneys
Carl Ludwig (mid 1800s) perfused an isolated kidney with 3% gum, 1% NaCl. The kidney did nothing. Jacoby (1892) perfused an isolated kidney with with aerated blood and obtained a very slow slow urine flow. The urine contained a lot of protein, indicative of tissue breakdown. By adding amyl nitrite to dilate the amyl arteries through which the aerated blood was perfused, Pfaff (1903) was able to get isolated kidneys to produce 16 ml of urine in 15 minutes. Ernest Starling, the discoverer of secretin, and the person who coined the term “hormone” also worked on the kidney
Ernest Starling (1924), taking into consideration the importance of convection convection, developed a fast moving aerated perfusion system that allowed an isolated kidney to produce over 30 ml of urine in 15 minutes, which was sufficient to begin to look for the localization of various functions in the tubules of the kidney. 5 Using an Isolated Kidney, Starling Discovered that Filtration Occurred at the Filtration Glomerulus
He observed that the rate of urine rate formation directly depended on the blood blood pressure. He compared the concentration of protein, CO2, urea, NH3, NaCl and Na2SO4 in the blood serum and in the urine and found that the small molecules entered the small tubules and the large molecules (e.g. large protein) and cells remained in the remained blood. Starling Discovered that Filtration is a Passive Process
He added cyanide, which inhibits the production of cyanide inhibits ATP ATP during cellular respiration, to the perfusion cellular solution in the renal artery. Then he compared the concentration of protein in the bl blood serum and the urine. After After short treatment times with cyanide, the urine still had no protein in it, indicating that filtration is a passive process passive process that does not require ATP. not require Protein Protein appeared in the urine after long treatment times because the kidney tissue itself began to break down. (ATP is necessary to maintain and rebuild the kidney). Filtration
The epithelial layers of epithelial the glomerulus and of glomerulus Bowman’s Bowman’s capsule have pores, and are pores thus leaky. leaky The The pores are large large enough enough to pass water, salts, sugar, amino acids, vitamins, and nitrogenous wastes, such as urea. The pores are too small too to pass proteins and blood cells. Active Secretion from the Capillaries to the Tubules
When the kidneys kidneys were perfused with cyanide cyanide, the amount of urea eliminated urea into into the urine decreased. decreased. Therefore urea in the urea capillaries must be actively actively secreted from the capillaries into the tubule in an ATPATP-dependent manner. Active Re-absorption from the Tubules to the Capillaries Summary of Kidney Function • Starling also found that the amount of NaCl eliminated into the urine increased after treatment with cyanide. • Therefore NaCl must be actively re-absorbed from the tubules and passed back to the capillaries in an ATP-dependant manner. Filtration Secretion ReRe-absorption Excretion 6 Determination of the Function of Specific Regions of the Tubule
It is now possible to isolate a small region of the renal tubule, perfuse it with solutions solutions of various radioactive radioactive tracers and measure the properties of the transport proteins responsible for moving the radioactive solutes across the epithelium of the tubule. ReRe-absorption of Glucose at the Proximal Tubule
The proximal tubule can transport up to 375 375 mg glucose/min out of the tubule. This is a high enough rate to re-absorb all reall the the glucose from the renal artery and send send it all back to the renal vein. But, But, this rate is not high enough to renot high reabsorb the high levels of glucose that occurs in the blood of diabetics. Thus diabetics diabetics end up with “sugary urine”, which is the literal meaning of diabetes diabetes mellitus. Diabetes and Sugary Flow
The The glucose in the collecting ducts of diabetics pulls water into the collecting ducts by osmosis by osmosis. This This leads to the production of excess urine and the need to urinate frequently. It It also causes diabetics to get thirsty and they to need to drink more often. Transport at the Distal Tubule
The distal tubule has membrane proteins distal that transport H+, K+ and ammonia (NH3) into the into the tubule so they will leave the blood and end up in the urine. The distal tubule also has membrane distal proteins that transport HCO3- out of the tubule so it can be re-absorbed and sent reback to the renal vein. The pH of the blood is maintained by balancing the transport of HCO3- out of HCO into the tubule and H+ into the tubule. 7 Concentration of Urine
The concentration of salts in urine is three times greater than the concentration of salts in the blood. To To concentrate the urine, water could be pushed through the ld differentiallydifferentially-permeable membranes along the length of the tubule in a process known as reverse osmosis reverse but but the amount of pressure needed would lyse the membranes. How then is the urine concentrated? The The Countercurrent Hypothesis
Werner Kuhn, a physical chemist who had experience in concentrating concentrating isotopes, isotopes, along with Bart Hargitay, had an Hargitay, idea how kidneys may concentrate urine using small and gentle pressures. The Loop of Henle Utilizes a Countercurrent Mechanism that Results in the Concentration of Urine
A countercurrent mechanism countercurrent due to the oppositely-directled, oppositely-directled, low pressure-induced flows pressurethrough through the Loop of Henle Henle establishes a gradient in the osmotic pressure in the medulla. The osmotic pressure at the top of the gradient is isotonic with isotonic the blood plasma while the osmotic pressure at the bottom of the gradient is hypertonic. hypertonic The Loop of Henle Helps Concentrate the Urine by Setting Up an Osmotic Gradient
The ascending loop of Henle is capable of actively pumping out NaCl. Since the ascending loop of Henle is NaCl. impermeable to water, water does not follow the NaCl out. The ascending fluid in this tubule, the interstitial ascending fluid of the medulla above and the distal convoluted tuble, tuble, which are in osmotic equilibrium, become become dil dilute. Since Since the descending loop of Henle is permeable to water but not to NaCl, the water leaves. The NaCl, descending descending fluid in the descending loop of Henle and the interstitial fluid of the medulla below, which are in osmotic equilibrium, become concentrated. become The countercurrent mechanism sets up an countercurrent sets increasing gradient of osmotic pressure in the medulla that is capable of pulling water out of the dilute pulling urine in the collecting ducts that pass through the medulla. Loop of Henle Animation The Collecting Duct Passes through the Medulla
The dilute urine in the collecting ducts pass through the hypertonic medulla medulla. The high osmotic pressure in the medulla is capable of pulling pulling water out of the collecting ducts. 8 3Cs: Conservation, Concentration and Convenience
In In this way the body conserves conserves water and concentrates concentrates the urine. Concentrating the urine, reduces the volume that needs to be excreted from about 200 liters to about 2 liters, which is a real convenience. convenience Using the Treasure House of Nature to Choose the Best Experimental System
In the animal kingdom, the length of the Loop of Henle is correlated with the dryness dryness of the environment. Consequently, Consequently, many studies on kidney function are done with desert animals, including the Syrian hamster. Carl Carl Gottschalk, Who Provided Evidence for the Countercurrent Hypothesis by Sampling Kidney Fluids with a Micropipette had a Kidney-Shaped KidneyDesk Carl Gottschalk Showed that the Conventional Wisdom Was Not Correct
When When asked by Carl Gottschalk, what he thought of the countercurrent hypothesis, Homer W. Smith (→), the titan of kidney the research research who believed that the fluid in the tubules got progressively concentrated, told him that “The smart boys don’t believe in it.” Carl Gottschalk worked in it anyways. Diuresis: Diuresis: The Production of Urine Urination, Micturition: Urination, Micturition: The Elimination of Urine Artists Often Recreate Biological Themes (Brussels, Belgium) Norway 9 In Tokyo In Prague The Balance Between Water Intake and Output Hormonal Control of Water Balance
If the intake of water is inadequate, the osmotic osmotic pressure of the blood will rise above the normal 285 mOsm and the and the body will become dehydrated become dehydrated. Dehydration is sensed by the hypothalamus which stimulates the posterior pituitary gland to secrete antidiuretic antidiuretic hormone (ADH or vasopressin). Dehydrations Sweating Respiratory water In milliliters per day Hormonal Regulation of Water Balance Antidiuretic Hormone: A Decrease in the Production of Urine • Antidiuretic hormone (ADH) prevents the production of urine. • ADH stimulates the insertion of proteinaceous water channels known as aquaporins into the collecting duct of the kidney. • This helps water move more readily out of the collecting duct and back into the interstitial fluid and the blood plasma instead of becoming urine and entering the ureters. 10 Negative Feedback Control of Water Balance Prevents Cell Lysing The "Hold Your Wee for a Wii" Challenge If the blood gets too dilute, the plasma and interstitial dilute fluid becomes hypotonic and the cells are at risk of hypotonic and swelling swelling and lysing. lysing When When the blood gets too dilute, ADH release is ADH reduced and the water channels in the collecting water duct are removed by endocytosis. removed Then the water is not re-absorbed into the blood restream but instead becomes urine. In January 2007, after competing in a contest to win a In after Wii, Wii, 28 year old Jennifer Strange was found dead. Jennifer tried to drink the most water without having to go to the bathroom. Jennifer died from drinking two gallons of water too quickly without urinating. Jennifer Jennifer died from water intoxication because the water ADH ADH concentration could not be lowered, and/or water channels channels could not be removed from her collecting ducts, fast enough. The Body has Functional Redundancy or Double Insurance Aldosterone Increases the Retention of Water by Increasing the Re-absorption of NaCl ReAldosterone increases re-absorption of reNaCl into the renal venules. This causes venules. an increase in the osmotic flow of osmotic water water into the blood stream. The The increased increased volume of blood that results will cause an increase in the blood pressure. The The blood pressure may increase even more if angiotensin II, a angiotensin vasoconstrictor vasoconstrictor, is also released. Many of the needs of the body are met by more than one system. Ensuring that the body has the correct volume of fluid (cell water, interstitial fluid and blood) is accomplished by the regulation of water channels by ADH and the water ADH regulation of NaCl re-absorption by aldosterone. NaCl realdosterone The Merits and Demerits of Aldosterone
During a prolonged “fight or prolonged flight” response, the adrenal adrenal glands secrete aldosterone. aldosterone Fortunately, the increased blood pressure pressure gives you the speed and and power you need to escape an attacking lion. Unfortunately, the higher the blood pressure, the greater the likelihood that a plaque will break off in an artery and result in a heart attack, stroke or pulmonary embolism. 11 Kidney Stones Form when the Concentrations of Salts in the Kidney Exceed their Ability to Stay in Solution and the Salts Crystallize
Calcium stones form when the concentrations of calcium and oxalic acid in the kidney are too high. Struvite Struvite stones form when the concentrations of th magnesium magnesium and ammonia are too high. Uric acid stones form when the concentration of uric acid is too high. Cystine stones occur when the concentration of cystine is too high. Kidney Stones can be Visualized in the Body with X-Rays X- Kidney Stones can be Painful
Stones may stay in the kidney or break loose. A small stone will travel through a ureter, the ureter bladder bladder and the urethra, urethra passing passing out of the body without causing much pain. A large stone can get stuck in the kidney, a ureter, the kidney ureter bladder bladder or the urethra. It urethra can block the flow of block urine and cause enormous enormous pain. 12 Kidney Stone Prevention
Drink more fluids to keep salts soluble. Avoid foods that are high in the salts that caused the kidney stones.
– Rhubarb is high in oxalic acid. – Meat is high in nitrogen that is a substrate to make uric acid Kidney Stone Treatments The kidneys connect to the ureters, which connect to the bladder. Double ureters occur in 1 out of 150 people. The bladder is drained via the urethra. Extracorporeal shock wave lithotripsy Ureteroscopic stone removal The Convenient Control of Urination When the bladder becomes full, stretch receptors in its wall stimulate the parasympathetic nerves which cause the smooth muscles that form the internal internal sphincter along the urethra to relax. The external The external sphincter, which is farther down the urethra and made of skeletal muscle, is under conscious control. This allows the convenience of the occasional release of stored urine where or when we choose instead of urinating with a continuous dribble. 13 The Composition of Urine The Color of Urine
Urobilins are a class of chemicals that are derived from the th breakdown breakdown product of hemoglobin hemoglobin. They give urine its yellowish color. The Smell of Urine
About forty percent of the population has the allele that codes for an enzyme that produces either that produces either methyl mercaptan from methionine or asparagine-aminosuccinic-acid monoamide from the asparagine found in asparagus. Yellow Energy
Ki Bang Lee designed a urine-powered micro urinebattery battery that can be used used to power disposable urine tests for diabetes and other diseases.
Small molecules like urea are removed from the blood because they are free to diffuse diffuse between between the blood and the bath fluid in the dialysis machine that contains the ideal mixture of salts and nutrients. Large molecules (e.g., plasma proteins) and cells remain confined to the blood. What happens when your kidneys can no longer filter your blood? can no longer filter your blood? 14 Kidney Transplants
Since a person only needs one working kidney, kidney transplants can come from living or dead donors. Are Are you an organ donor? Check the back back of your driver’s license. Dr Joseph Murray (1990) of the Peter Bent Brigham Hospital in Boston won the Nobel Prize for working out the immunosuppressant techniques necessary for successful transplants between immunologically immunologically different people. Selling Kidneys
This man could buy a car with th t he $10,000 $10,000 he got for selling one of his kidneys.
Newsweek 1/19/09 The Global Kidney Economy The Global Kidney Economy Pakastani Kidney Tourist Trade One Kidney Island in the Phillipines Donating Priceless Kidneys The Kidneys Also Regulate Red Blood Cell Production
Erythropoietin (EPO) is a peptide hormone hormone produced by the kidneys and secreted into the blood blood stream in response to to lowered oxygen levels. Erythropoietin stimulates the bone marrow to bone make more oxygenoxygencarrying red blood cells. red A low red blood cell count results in anemia and low anemia endurance. donatelifeny.org www.health.state.ny.us alliancefordonation.org 15 GeneticallyGenetically-engineered human erythropoietin is used to help people with chronic kidney disease fight anemia that results from too few red blood cells. Endurance Athletes: Live High-Train HighLow Procrit Epogen Living where the “air is thin” for 4 weeks causes one to produce more erythropoietin. erythropoietin The additional red blood cells then gives an red endurance athlete a 2-3% advantage. 2- Increase Increase Your Erythropoietin Concentration While You Sleep
If If you cannot go to the mountain, the mountain can come come to you in the form of a low oxygen (hypoxic) chamber in which you can sleep.
Hypoxico But, does Every Individual Have the Right to Have a High Level of Erythropoietin?
Does a person with damaged kidneys have the right? Do the parents of a particular embryo, created by in vitro fertilization, which in upon testing shows that it is likely to express low levels of erythropoietin and destined to be anemic have the right to request that the embryo be transformed with erythropoietin genes? Does an endurance athlete have the right to inject himself/herself with EPO to increase his/her endurance? Cheating (and Testing) in Sports From Fish to Philosopher: Homer W. Smith
“No less than his lowly predecessors, he continues in the search of the free and independent life, for it is in the nature of all life to move into that equilibrium where the the totality of desire is balanced against the the totality of restraint. But because he is the highest vertebrate he can do what no other vertebrate can do: when, out of whatever desire and knowledge may be his, he makes a choice, he can say ‘I will…’ And knowing how and why he says ‘I will” he comes into his own as a philosopher.” Blood doping at the 2007 Tour de France Cheats inject EPO, which increases the oxygenoxygencarrying capacity of the blood. Athletes are now screened and tested for EPO. 16 In Part, Our Freedom Depends on Our Kidneys Working Hard to Ensure the Constancy of Our Internal Milieu
Have You Thanked Your Kidneys Today? Today? 17 ...
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This document was uploaded on 11/09/2010.
- Spring '07