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Formation and Excretion of Urine outline I. Functional renal anatomy II. Renal blood flow III. Glomerular filtration IV. Transport in the renal tubule and collecting duct V. Urinary concentration and dilution VI. Regulation of urine formation VII. Clearance VIII.Renal regulation of acid-base balance IX. Micturition Excretion pathway Respiratory system Large intestine Skin Kidney Excretory Approach Urinary System General principles Kidney Functions** • Kidneys regulate water and electrolyte levels. • Kidneys regulate acid-base balance. • Kidneys excrete metabolic waste products and foreign substances. • Hormones produced are angiotensin Ⅱ,1, 25dihydroxyvitamin D3, aldosterone and erythropoietin(EPO). Body water homeostasis (balance) I. Functional renal anatomy • The nephron is the basic subunit of the kidney. It is composed of two components: the glomerulus and the renal tubule. • Renal arterioles lead to glomerular capillary tufts, which are the site of blood filtration. • Bowman’s capsule receives this filtrate, which is modified as it passes along the kidney tubules. • A single kidney is divided into four major sequential sections: Proximal tubule, loop of Henle, distal tubule, and collecting duct, each with unique characteristics. • Capillaries surround kidney tubules enabling exchange between blood and tubular fluid. 1.Basic kidney structure 2. Nephron structure Renal Tubules Nephron is composed of two components: the glomerulus and the renal tubule. Nephron structure Nephron is composed of two components: the glomerulus and the renal tubule. Nephrons can reach to renal medulla • Cortical nephron • The nephrons have their glomeruli located in the outer and middle portion of the renal cortex are called cortical nephrons. • Juxtamedullary nephron • The nephrons have glomeruli that lie deep in the renal cortex near the medulla and have long loops of Henle that are deep into the medulla are called juxtamedullary nephron. 3. Glomerulus — Called Capillary Tufts Under the Electronic Microscope Glomerulus Blood Out Blood In Relationship visualized as a fist (Glomerulus, in) and a balloon (Bowman`s capsule, out) juxtaglomerular apparatus • The juxtaglomerular apparatus consists of the juxtaglomerular cells, the macula densa and the extraglomerular mesangial. juxtaglomerular cell • The juxtaglomerular cells are specialized myoepithelial cells in the media of afferent arteriole close to the glomerulus. Juxtaglomerular apparatus – JG cells can secrete Renin. – JG cells serve as baroreceptor in afferent arteriole. 4. Glomerular filtration membrane The epithelial cells of Bowman`s capsule called Space porous • Glomerular filtration membrane • The barrier between the capillary blood and the fluid inside the Bowmen's capsule is called glomerular filtration membrane. Glomerular filtration membrane Glomerular filtration membrane is impermeable to blood cell and plasma protein. Pores 5. Renal tubule The renal tubule is divided into four sections: proximal tubule, loop of Henle, distal tubule and collecting duct. (Glomerulus ) renal corpuscle (Bowman capsule) proximal convoluted tubule proximal tubule Nephron renal tubule henle loop distal tubule Collecting duct distal convoluted tubule II. Renal blood flow (RBF) Renal blood flow distribution 95% Renal blood flow (RBF) Renal blood flow distribution 1. A second capillary networks called the peritubular capillaries a first capillary network a second capillary network These capillaries surround specific segments of the tubule, and they return water and substances reabsorbed by the tubule to the general circulation, as well as deliver needed nutrients to the tubule. Peritubular capillaries Under the electronic microscope Higher plasma colloid osmotic pressure in the peritubular capillaries is in favor of tubular reabsorption. 2. vasa recta 3. Characteristics of renal blood flow ** ! Large blood flow:400 ml/min·100g Renal blood volume ! Maldistribution of blood flow : renal papilla (1%) <renal medulla (5%)<renal cortex (94%) ! Primary and secondary capillary networks # glomerular capillary network (primary network) (between afferent glomerular arteriole and efferent glomerular arteriole, high blood pressure,in favour of glomerular filtration) #peritubular capillary network (secondary network) (made by branch of efferent glomerular arteriole, low blood pressure, in favour of tubular reabsorption) Autoregulation of renal blood flow Tubuloglomerular feedback Nervous and humoral regulation 4. Determinants and regulation of RBF • RBF is determined by systemic arterial blood pressure and renal vascular resistance (renal sympathetic vasoconstrictor nerve control). • RBF demonstrates autoregulation. • Autoregulation involves afferent not efferent arterioles. • Autoregulation is explained either by the myogenic hypothesis or tubuloglomerular feedback. Autoregulation of RBF and GFR Autoregulation means simply regulation of blood flow by Rena the tissue itself. Whenever on excessive amount of blood l flows through a tissue., the local vasculture constricts and Bloo decreases the blood flow forward to normal. d Flow or Glo meru lar Filtra tion Rate Glomerular Filtration Rate Renal Blood Flow (RBF) 80 150 Systemic Arterial Pressure (mm Hg) The kidney maintains a constant blood flow (autoregulation) and glomerular filtration rate over the physiological range of systemic arterial pressure. Autoregulation of RBF and GFR Mechanism of autoregulation Two hypotheses describe autoregulation: myogenic and tubuloglomerular feedback. •1.The myogenic hypothesis: When systemic arterial pressure increases RBF, the afferent arterioles are stretched. This stretch stimulates them to contract increasing their resistance and maintaining a constant RBF. If RBF decreased, then the opposite would occur. •2. Tubuloglomerular feedback involves an interaction between the distal tubules and the afferent arterioles. The beginning portion of the distal tubule passes close to the afferent arteriole, and together they form a specialized structure called the juxtaglomerular apparatus. Specialized epithelial cells in this portion of the distal tubule, called macula densa cells, sense the amount of NaCl (sodium chloride) in the tubular fluid. With an increase in RBF there will be an increase in GFR, an increase in filtration, and an increase in the amount of NaCl passing by the macula densa cells. In response to this increased NaCl, a yet unidentified substance is released that causes afferent arteriolar constriction. This constriction reduces RBF, GFR, and the amount of NaCl delivered to the macula densa cells. If RBF were to decrease, then the opposite would occur. Tubuloglomerular feedback NaCl NaCl 5. Nerve innervation of kidney Renal sympathetic vasoconstrictor nerve control the smooth muscle of afferent glomerular arteriole and efferent glomerular arteriole, renal tubule and juxtaglomerular cell. – Vasoconstriction and RBF regulation – Increased reabsorption of Na+、Cl-, etc., in the renal tubular epithelial cell –control juxtaglomerular cell to release renin Kidney have no vagus nerve fibers innervation Renal afferent nerve fibers act on mechanical and chemical stimulation toward central nervous system. Process of urine formation Three steps: Glomerular filtration Renal tubule/collecting duct reabsorption Renal tubule/collecting duct secretion and excretion Material transport of renal tubule/collecting duct III. Glomerular filtration Glomerular filtration rate (GFR) Effective filtration pressure (EFP) Factors affecting glomerular filtration rate Regulation of GFR Interaction between renal blood flow (RBF) and GFR Basic renal terminology * • Glomerular filtration rate (GFR) is the amount of fluid moving into Bowman’s capsule per unit time (min). • Renal blood flow (RBF) is the amount of blood flowing through the kidney per unit of time (min). • Filtration is the process by which substances enter Bowman’s capsule. • Reabsorption is the process by which substances move from inside to outside the tubule. • Secretion is the process by which substances move from outside to inside the tubule. • Excretion refers to substances that pass from the kidney into the bladder. • it is the ability of the kidney to selectively move specific substances into and out of the tubule in a very controlled and coordinated manner that makes normal kidney function so critical to life. Explanation for some terms 1. Glomerular filtration rate (GFR) •Glomerular filtration* Filtration is the process by which substances enter Bowman’s capsule. •Glomerular filtration rate, GFR* It is the amount of fluid moving into Bowman’s capsule per unit time (min). •glomerular filtration fraction, GFF* The glomerular filtration fraction is the filtration rate as percentage of the total renal plasma flow that passes through both kidneys. 2. Factors affecting glomerular filtration rate • Effective filtration pressure • Filtration coefficient,Kf (1) Glomerular effective filtration pressure •The effective filtration pressure of glomerulus represents the sum of the hydrostatic and colloid osmotic forces that either favor or oppose filtration across the glomerular capillaries. Formula*: Effective filtration pressure = Glomerular capillary pressure -( Plasma colloid osmotic pressure + intracapsular pressure ) (2) Filtration coefficient,Kf •Under the effective filtration pressure (EFP) driving force, liquid volume passing through filtration membranes per unit time. •Two determinants of Kf: filtration membranes area (s) permeability coefficient of filtration membranes (K) Kf = k× s 3. Factors affecting glomerular filtration** Change of effective filtration pressure Change of filtration coefficient GFR= Kf × S × (PGC-πGC-PBC) EFP GFR: glomerular filtration rate S: Kf : PGC: glomerular capillary pressure permeability coefficient glomerular filtration membrane area πGC: plasma colloid osmotic pressure PBC: hydrostatic pressure in bowman Changes in renal blood flow Determinants and regulation of GFR and RBF • GFR is determined by the balance of forces acting across the filtration membrane. The forces that drive fluid out of the glomerulus are the capillary blood pressure (PGC) and the osmotic pressure (∏BC) of the fluid in Bowman’s capsule. The forces driving fluid into the glomerulus are the hydrostatic pressure (PBC) of the fluid in Bowman’s capsule and the osmotic pressure (∏GC) of the blood within the glomerulus. The difference between these four forces determines the net filtration pressure, which is approximately 15 mm Hg. • Net filtration pressure* = (PGC +∏BC) - (PBC +∏GC) = (55+0)-(15+25) = 15 mm Hg ∏BC is zero. Explanation • Filtration coefficient (Kf), a factor reflects permeability of filtration membrane. Net filtration pressure 4. Regulation of GFR •Changes in systemic arterial pressure, the radius of the renal arterioles, and the filtration coefficient normally regulate GFR. 1. If systemic arterial pressure increases, then the pressure in the glomerular capillaries will increase and GFR will increase. The opposite will happen if systemic arterial pressure decreases. 2. Renal arteriolar resistance. (see next illustration) 3. Filtration coefficient—The filtration coefficient can be altered by the contractile activity of an additional set of cells located among the podocytes. These cells are called mesangial cells. These cells can be stimulated to contract, and when this occurs they decrease the area available for filtration and thus decrease the filtration coefficient and GFR. 4. Clinic diseases: Starvation / Burn → GFR↑,Renal Stones → GFR↓ 5. Interaction between RBF and GFR As discussed above, an increase in efferent arteriolar resistance produces opposite effects on RBF and GFR. RBF decreases and GFR increases. Under normal situations, blood leaving the glomerular capillary bed is at a higher osmotic pressure (∏GC) than the blood entering because of the fluid lost as ultrafiltrate. This rise in ∏GC is not sufficient to significantly limit GFR. However, with a large increase in efferent resistance, RBF is reduced enabling ∏GC to increase to such an extent that GFR is reduced. Therefore, GFR does not increase as much as expected with an increase in efferent arteriolar resistance because of the relationship between GFR, RBF, and ∏GC. Regulation of GFR with different arteriolar diameters PGC Decreased Afferent Arteriolar Diameter GFR Glomerular Capillary PGC Decreased Efferent Arteriolar Diameter GFR Changes in arteriolar resistance before (afferent) and after (efferent) the glomerular capillary bed have different effects on capillary hydrostatic pressure (PGC) and therefore on glomerular filtration rate (GFR). Effects of different arteriolar resistance on GFR Effects of different arteriolar resistance on GFR Effects of different arteriolar resistance on GFR Effects of different arteriolar resistance on GFR Nervous and humoral regulation of RBF and GFR Nervous regulation: Renal sympathetic nerve: Hypovolemia, noxious stimulation or agitation, etc.→sympathetic nervous activity↑→ afferent glomerular arteriole contraction→ RBF and GFR↓; Hypervolaemia→sympathetic nervous activity ↓ → afferent glomerular arteriole dilatation → RBF and GFR↑. Humoral regulation: epinephrine, norepinephrine, vasopressin, angiotensinⅡ — Renal vasoconstriction decreases RBF. prostaglandin, NO, ANP, bradykinin, endothelin — Renal vasodilatation increases RBF. Summary • Urine formation starts with the filtration of plasma in the kidney. • Glomerular filtration is favored by the high hydrostatic pressure of the blood in the glomerular capillaries and is opposed by the hydrostatic pressure in the urinary space of Bowman’s capsule and by the glomerular capillary colloid osmotic pressure. • Glomerular filtration is rather nonselective; proteins are mostly retained in the plasma by the glomerular barrier, but all low-molecular-weight substances are freely filtered. • Key terms: GFR, EFP, FF, Autoregulation IV. • • • • • Transport in the renal tubule and collecting duct 1. Overview of tubule properties Permeability properties of the luminal and basolateral membranes of the epithelial cells lining renal tubules are different, enabling directional movement of salt and water. Proximal tubule reabsorbs isotonically a constant 60% of the GFR. Loop of Henle reabsorbs more salt than water. Distal tubule continues to reabsorb more salt than water. Permeability of the collecting duct to salt and water is hormonally controlled by antidiuretic hormone (ADH) and aldosterone. [dilute urine / concentrated urine] Reabsorption and secretion in the renal tubule and collecting duct Definition •Transport • ! Renal tubular reabsorption* Tubular reabsorption denotes the transport of substances from the tubular fluid through the tubular epithelium into peritubular capillary blood. • ! Secretion of the renal tubule and collecting duct Product made by epithelial cells itself or blood substance are transported into renal tubular lumen. •Transport patterns: ! Passive transport: diffusion, permeation, facilitate diffusion, solvent daggling ! Active transport: sodium pump, hydrogen pump, calcium pump (symport or antiport) •Transport pathway: – Paracellular pathway – transcellular pathway 2. Reabsorption of the renal tubule and collecting duct General situation • Proximal tubule reabsorbs 67%of the filtered Na+, Cl- and H2O • Proximal tubule is the only site for glucose reabsorption • Loop of Henle reabsorbs 20% of the filtered Na+ and Cl- • The luminal cell membrane of the thick ascending limb contains a Na+-k+-2Cl- cotransporter • The distal tubule and collecting duct reabsorb 12% of the filtered Na+ and Cl- Renal tubule reabsorption of salt and water 3. Proximal tubule reabsorption of salt and water • NaCl reabsorption is dependent upon the coordinated action of the Na-K-ATPase on basolateral membrane of the epithelial cell and several facilitated transport systems on the luminal membrane of the epithelial cell. • Water reabsorption follows and is dependent upon Na ion reabsorption. • Water reabsorption is assisted by the elevated osmolarity of the peritubular capillary blood. Proximal tubule reabsorption of salt and water Proximal Tubular Cell Na+ B L O O D Glucose & amino acids Na+ ATP K+ Cell 1 H+ Cell 2 Basal lateral membrane Na+ T U B U Water L A R FL UI Luminal membrane D The major mechanisms by which molecules move across the epithelium of the proximal tubule are diagramed in this figure. Proximal tubule reabsorption of + Na Proximal tubule reabsorption of salt and water 4. Proximal tubule reabsorption of glucose and amino acids • Reabsorption of glucose and amino acids is coupled to the reabsorption of Na ions. • Glucose reabsorption is overwhelmed when blood glucose is very high (diabetes). [daiebi:ti:z, -ti:s] Proximal tubule reabsorption of glucose Proximal tubule reabsorption of glucose Relationship between plasma glucose and filtration rate of glucose Relationship between plasma glucose and reabsorption rate of glucose Relationship between Plasma Glucose and Excretion Rate of Glucose renal glucose threshold* When the plasma glucose concentration increases up to a value about 180 to 200 mg per deciliter, glucose can first be detected in the urine, this value is called the renal glucose threshold. Summary about Glucose Graph Questions 5. Proximal tubule reabsorption of bicarbonate ions • Bicarbonate reabsorption requires Nadependent H ion secretion. • Bicarbonate reabsorption occurs indirectly through the formation of CO2 and H2O. Proximal tubule reabsorption of bicarbonate ions B L O O D Na+ + HCO3- Na+ HCO3- + H+ H+ + HCO3- H2CO3 CA H2O + CO2 H2CO3 CA CO2 + H2O T U B U L A R FL UI D Reabsorption of bicarbonate ions in proximal tubule requires the formation and breakdown of carbonic acid (H2CO3) within the tubular fluid and epithelial cells. The enzyme carbonic anhydrase (CA) is essential for this process to occur. Some diuretics work by inhibiting the carbonic anhydrase enzyme. Proximal tubule reabsorption of bicarbonate ions 6. Loop of Henle reabsorption of salt and water • Descending limb of the loop of Henle is permeable to water but not to salt. • Ascending limb of the loop of Henle is permeable to salt, because of a Na-K-Cl ion tritransporter, but not to water. • Reabsorption of water from the descending limb results from the reabsorption of salt by the tritransporter in the ascending limb. Loop of Henle reabsorption of salt and water Ascending limb of the loop of Henle: a Na-K-Cl ion tritransporter for reabsorption of salt Tubular Lumen Fluid Blood Na+-2Cl--K+ tritransporter Tubule epithelial Cell CELL Place is the ascending limb of the loop of Henle Counter-current multiplication • An osmotic gradient is established in the interstitial space surrounding the loop of Henle that increases from the top to the bottom of the loop. • The action of the tritransporter of the epithelial cells of the ascending limb, the water permeability of the descending limb, and the shape of the loop contribute to the development of this osmotic gradient. • The process by which this occurs is called countercurrent multiplication. Counter-current dissipation Counter-current exchange Counter-current multiplication Assuming that initially all fluid within the loop has the same osmolarity (panel A) the tritransporter will reabsorb Na, K, and Cl from the tubular fluid creating an osmotic gradient of 200 mOsm between the interstitial space and the tubular fluid. The ascending limb is not permeable to water so water cannot follow. The descending limb is not permeable to salt so it cannot enter from the interstitial space. However, the descending limb is permeable to water so water is reabsorbed into the interstitial space. A new steady state is established (panel B). At this point new fluid enters from the proximal tubule displacing the fluid within the loop. This disrupts the steady state (panel C).Through the reabsorption of salt by the ascending limb and water by the descending limb, a new steady state is established (panel D). Notice that an osmotic gradient is being established in the interstitial space from the top to the bottom of the loop. It is the result of the loop structure and the different permeabilities of the two limbs of the loop. Fluid leaving the ascending limb is hypotonic compared to the fluid entering because more salt than water is reabsorbed. We will see in a later section that the interstitial osmotic gradient is critical for water reabsorption. A B Equilibrium State 300 300 300 400 400 200 Water 300 Reabsorption 300 300 400 400 200 400 400 200 300 300 300 400 400 200 300 300 300 Na-K-Cl 400 400 Reabsorption 200 C D Equilibrium State 300 400 200 350 350 150 300 400 200 350 350 150 350 350 150 400 400 400 400 400 500 500 300 400 500 500 300 400 400 Increasing Osmotic Gradient The shape and permeability properties of the loop of Henle enable an osmotic gradient to be established within the kidney. Diagrams A through D show in a step-wise manner how the gradient is established. Counter-current exchange of vasa recta 7. Distal tubule reabsorption of salt and water • More salt than water is reabsorbed. • Na and Cl ions reabsorbed together. The distal tubule retains some of the properties of the ascending limb of the loop of Henle in that it is not very permeable to water and reabsorbs Na and Cl ions. The reabsorption of Na and Cl ions occurs through a co-transport carrier protein on the luminal side of the epithelial cell that combines the movement of one Na and Cl ion into the cell. This reabsorption is driven by the Na ion concentration gradient established by the Na-K-ATPase on the basal lateral side of the epithelial cell. Distal tubule reabsorption of salt and water Tubular Fluid Tubule epithelial Cell Lumen Tubule epithelial Cell Symporter Tubule epithelial Cell Blood 8. Collecting duct reabsorption of salt and water • The permeability of the collecting duct to Na ions and water is variable. • Antidiuretic hormone (ADH or Vasopressin, VP) increases the permeability of the collecting duct to water. • Aldosterone increases the reabsorption of Na ions by the collecting duct. Collecting duct reabsorption + of Na Tubular Lumen Fluid Blood Epithelial Cell of the Collecting Duct Epithelial Cell of the Collecting Duct Effect of antidiuretic hormone (ADH) on the permeability of the collecting duct to water ADH release Epit heli al Cell of the Coll ecti ng Duc t Concentrated Urine Effect of antidiuretic hormone (ADH) on the permeability of the collecting duct to water ADH not release Epit heli al Cell of the Coll ecti ng Duc t Dilute Urine Antidiuretic Hormone (ADH or vasopressin, VP) Mechanism of ADH or VP in the collecting duct for water reabsorption Antidiuretic hormone, also known as vasopressin, a posterior pituitary hormone, increases the number of aquaporin channels in the membrane of the epithelial cells increasing water reabsorption. In the presence of ADH, water can leave the collecting duct in response to the osmotic gradient. Relationship between plasma osmolarity and plasma vasopressin Mechanism of aldosterone in the + collecting duct for Na reabsorption Epithelial Cell of the Collecting Duct Epithelial Cell of the Collecting Duct Aldosterone,a hormone secreted by the adrenal cortex, acts on collecting duct in several ways to increase Na reabsorption. 9. Collecting duct secretion of K and H ions •The collecting duct secretes both K and H ions. •K and H ion secretion is sensitive to aldosterone. K ions are secreted through channels located in the luminal membrane of specialized epithelial cells of the collecting duct called principle cells. This secretion is down a concentration gradient established by the Na-K-ATPase located on the basolateral membrane. In the presence of aldosterone, more channels are opened and secretion is increased. Specialized cells of the collecting duct, called intercalated cells, are responsible for H ion secretion. This secretion is due to an active transport process that moves H ions from the inside of epithelial cell to the tubular fluid. The activity of this transporter is increased by aldosterone. Collecting duct secretion of K and H ions Tubular Lumen Fluid Epithelium of the Collecting Duct principle cell Channels + aldosterone Cl- intercalated cell + aldosterone Epithelium of the Collecting Duct Blood 10. NH3 secretion is related to H+and HCO3transport • 60% of NH3 secretion from glutaminate , 40%from glycine • NH3 secretion promotes H+ secretion and HCO3reabsorption, in favor of renal acids excretion and alkaline reabsorption. NH3 NH4 NH3 V. Urinary concentration and dilution • Urinary dilution • Urinary concentration • The loops of Henle are countercurrent multipliers • The vasa recta are countercurrent exchangers • Urea plays a special role in the concentrating mechanism 1. Overview • urinary concentration • The basic requirements for forming a concentrated urine are a high level of ADH and a high osmolarity of the renal medullary interstitial fluid. • urinary dilution • The mechanism for forming a dilute urine is continuously reabsorbing solutes from the distal segments of the tabular system while failing to reabsorb water. Urinary concentration and dilution 2. Definition • Plasma osmotic pressure (POP):300 mmol/L( 300mOsm/kg H2O) • Urine osmotic pressure>POP, hypertonic urine —Concentrated urine, 1200 mmol/L • Urine osmotic pressure <POP, hypotonic urine —Diluted urine, 50 mmol/L • Urine osmotic pressure =POP, isosthenuria —Urinary concentration and dilution of kidney is damaged. 3. Mechanism of urinary concentration and dilution • Urinary concentration Forming mechanisms of hypertonicity in the medulla Countercurrent multiplication of Henle's loop Countercurrent exchange of vasa recta Counter-current theory vasa recta • Countercurrent multiplication • Countercurrent multiplication is the process where by a small gradient established at any level of the loop of Henle is increased (multiplied) into a much larger gradient along the axis of the loop. Process of urinary concentration and dilution VI. Regulation of urine formation • • • • • • Autoregulation of urinary formation Glomerulotubular banlance Effect of renal sympathetic nerve Effect of antidiuretic hormone Renin-angiotensin-aldosterone system Effect of atrial natriuretic peptide 1. Regulatory patterns and Significance •Regulatory patterns: Autoregulation Nervous regulation Humoral regulation •Significance: Maintenance of internal environment homeostasis. 2. Autoregulation in kidney • osmotic diuresis – Solute concentration of renal tubular fluid – Mannitol (clinic use) – Different from water diuresis * The volume of urine increases when water intake exceeds body needs, it is resulted from suppression of ADH secretion. • Glomerulotubular balance • One of the most basic mechanisms for controlling tubular reabsorption is the intrinsic ability of the tubules to increase their reabsorption rate in response to increased tubular inflow. This phenomenon is referred to as glomerular-tubular balance. 3. Nervous regulation • Renal sympathetic nerve – αreceptor activation contracts afferent and efferent glomerular arteriole inducing decreased RBF and GFR . – αreceptor activation increases proximal convoluted tubule reabsorbing Na+ and other solutes; – β receptor activation promotes juxtaglomerular cell releasing renin; • Homeostasis of Na+and water maintained. • Renal sympathetic nerve involved in reflex: – cardiopulmonary receptor reflex; – Kidney – Kidney reflex. 4. Humoral regulation • Renin-angiotensin-aldosterone system,RAAS • Renal kallikrein-kinin system • Atrial natriuretic peptide,ANP • Endothelin,ET • Nitric oxide,NO • Vasopressin,VP Antidiuretic hormone,ADH • Catecholamine, CA • Prostaglandin, PG Renal regulation of salt and water balance Sensing alterations in salt balance • Salt balance, principally NaCl concentration, is assessed by monitoring osmolarity. • Salt levels are changed by adjusting water reabsorption through the action of antidiuretic hormone (ADH). • ADH* increases the number of open aquaporin channels in the collecting duct thereby increasing water reabsorption. Renal regulation of salt and water balance [NaCl]o↑ Cells shrink Signal to Sensing alterations in water balance • Water balance is assessed by monitoring blood volume through changes in blood pressure. • Water levels are changed by adjusting salt reabsorption through the renin-angiotensin-Ⅱ-aldosterone system. • Increased sympathetic nerve stimulation directly increases renal secretion of renin. • Decreased distal tubule Na-load directly stimulates renal renin secretion. • Increased volume stimulates the secretion of atrial natriuretic peptide form the atria. Sensing alterations in water balance Sensing alterations in water balance Renin-Angiotensin-Ⅱ-Aldosterone system (R-A-A-S). + Increased sympathetic nerve stimulation directly increases renal secretion of renin. Angiotensin-Ⅱalso directly stimulates Na+ reabsorption by cells of the proximal tubule. - Effects of ANP on kidney • Dilatation of afferent glomerular arteriole increases GFR and Na+ in tubular fluid; • Inhibiting Na+ channel on the collecting duct epithelium with help of cGMP decreases Na+ and water reabsorption at the collecting duct; • Inhibiting renin release reduces ANGⅡ and aldosterone secretion, then indirectly inhibits Na+ reabsorption • Inhibiting ADH secretion induces kidney water drain increasingly. Sensing alterations in water balance Renal regulation of salt and water balance ── Relationship of osmolarity and volume 5. Reflex response to dehydration* Dehydration results from an imbalance between water intake and water loss • Dehydration initiates reflexes to conserve both salt and water . • Dehydration reduces blood pressure , which reduces GFR and RBF independent of other factors. • Baroreceptor-regulated increased sympathetic nerve activity activates the renin-angiotensin- Ⅱaldosterone system and decreases GFR and RBF. • Osmoreceptors stimulate the release of ADH. • Sense of thirst is stimulated. Reflex response to dehydration * With sweating (running) induced dehydration→water volume↓and osmolarity↑→blood pressure↓→GFR,RBF↓→water and salt excretion↓ Blood pressure↓→baroreceptor –mediated reflex response→ sympathetic nerve activity↑→R-A-A-S↑→water and salt reabsorption↑→diminish dehydration Sympathetic nerve activity↑→afferent arteriolar constriction→ GFR,RBF↓→ diminish dehydration Blood pressure↓→GFR and the distal tubule Na﹢load↓→The distal tubular epithelial cells stimulate→renin↑→R-A-A-S↑ Extracellular osmolarity↑→ADH release↑→water reabsorption↑ Water volume↓and osmolarity↑→thirst occurs→drink water VII. Renal clearance Research method of kidney function Renal clearance ** •The volume of plasma per unit time needed to supply its quantity of substance excreted in the urine per unit time. Clearance* • • • • Clearance used to measure GFR and RBF Clearance is based on the principle of conservation of mass. Clearance is the volume of blood per unit of time that had all of a particular substance removed by the kidney. The clearance formula is Cx = (VU×[X]U) / [X]p The clearance of substances with specific properties enables one to determine GFR and RBF. Clearance for use 1 g/mL Glomerular Capillary Efferent Arteriole Afferent Arteriole Bowman`s Capsule 125 mL/min 125 g/min Proximal Tubule Peritubular Capillary 1 mL/min 125 g/mL 125 g/min Urine × This figure illustrates the principle of clearance and how it can be used to determine glomerular filtration rate. Clearance = GFR • Creatinine, that is normally present in the blood and is not reabsorbed and minimally secreted by the kidney. By measuring urine flow rate and the concentration of creatinine in the blood and urine, the GFR can be calculated. Because of the characteristics of creatinine, you can say that the clearance of creatinine is the GFR. • The clearance equation: Cx = (VU×[X]U) / [X]p Urea clearance Glucose clearance Penicillin clearance Clearance for use • The clearance equation can also be used to calculate renal plasma flow (RPF) if a substance with an additional property is used. This additional property is that all of it needs to be removed from the blood by the kidney through a combination of filtration and secretion. • Para-aminohippuric acid (PAH) clearance equals the RPF. • RBF = RPF / (1 - Hct). (hematocrit, Hct) Significance of renal clearance •Estimate renal function; •Determine glomerular filtration rate (GFR ) •Determine renal blood flow (RBF) •Presume renal tubular transport effect •Free-water clearance Afferent arteriole •微穿刺和微 灌流技术 Bowman capsule Distal convoluted tubule Efferent arteriole Glomerulus •(micropuncture) VIII. Renal regulation of acid-base balance General considerations • Metabolism of food generates acid. • Acid in the body is in two forms: fixed and volatile. • Kidneys remove excess fixed acid; lungs remove excess volatile acid. • Acidemia is excess H ions in the blood; alkalemia is excess bicarbonate ions in the blood. Renal regulation of acid-base balance • Normal Blood pH Value 7.35-7.45 • CO2 + H2O H2CO3 H+ + HCO3-, H+ is volatile acid • Increasing ventilation will blow off more CO2 driving the reaction to the left and lowering the H+ concentration. • Decreasing ventilation will allow CO2 to accumulate driving the reaction to the right and increasing the H+ concentration. • Other acids named fixed acids. (such as sulfuric and phosphoric acids ). • Kidneys role (keeps appropriate level of bicarbonate ions / excretes the fixed acids produced by the body / secretes hydrogen ions). • Lungs role (ventilation controls CO2 adjusting [H+] ). • When the blood contains excess H ions the condition is called acidemia (acidosis ). Diarrhea • When the blood contains excess bicarbonate ion, the condition is called alkalemia (alkalosis). Vomiting Renal regulation of acid-base balance Renal production of bicarbonate ions • The kidney produces bicarbonate through the formation of titratable acid. • The kidney produces bicarbonate through the metabolism of glutamine. Renal production of bicarbonate ions (Disodium salts) Na2HPO4 T Renal Tubular Na++NaHPO4- U Epithelial Cell Glutamine →NH3 B NH3+H+ Na+ U L + + + H HCO3 + H H H + NaHPO4 A Carbonic acid R (Monosodium salts) NaH PO 2 4 (H2CO3) FL UI Urine Formation of titratable acid in the proximal tubule is one way by whichD the kidney B L O O D generates new bicarbonate ions in response to acidemia. The H+ ion secreted by the epithelium is excreted as NaH2PO4 (titratable acid) leaving a bicarbonate ion behind. Renal production of bicarbonate ions Renal production of bicarbonate ions Tubular Lumen Fluid Epithelium of the Collecting Duct Blood (New HCO3- ) Epithelium of the Collecting Duct Renal production of bicarbonate ions Renal secretion of H ions Tubular Lumen Fluid Epithelium of the Collecting Duct principle cell Blood [H+]=4×10-8 M pH=7.4 Channels + aldosterone Cl- Pump [H+]=3×10-5 M intercalated cell + aldosterone pH=4.5 Epithelium of the Collecting Duct • H ion secretion in the collecting duct leads to acidification of the urine. • Collecting duct H ion secretion is stimulated by aldosterone. Renal compensation for alkalemia When the blood contains excess base, the kidney excretes bicarbonate and does not generate additional bicarbonate. Increase bicarbonate excretion occurs because there are insufficient H ions to be secreted by the proximal tubules to reabsorb all the filtered bicarbonate. The excess bicarbonate is excreted. Also, the low level of H ions means that filtered sulfuric and phosphoric acids will not be titrated and so no additional bicarbonate will be generated. In these ways, the kidney attempts to lower the blood bicarbonate concentration compensating for the alkalemia. Renal compensation for alkalemia Renal compensation for acidemia When the blood contains excess H ions, the kidney excretes H ions and generates additional bicarbonate. In the presence of excess H ions, there are plenty of H ions to reabsorb all the filtered bicarbonate. In addition, the filtered fixed acid will be titrated generating additional bicarbonate ions. Also, the excess H ions stimulate the metabolism of glutamine by the kidney and the production of even more bicarbonate. Finally, the collecting duct increases its secretion of H ions. The combined effects of complete bicarbonate reabsorption , new bicarbonate generation, and the secretion of H ions helps the body compensate for the acidosis. Renal compensation for acidemia concentration Relationship Between plasma K Ion Concentration and Acid-base Status • Increase in plasma levels can lead to acidemia. • Increase in plasma H+ levels can lead to hyperkalemia. • Plasma K+ levels can compromise the + ability of the kidney to regulate H excretion. + K A relationship exists between the K and the H ion levels of the blood • [ K+]o↑(hyperkalemia) → [ K+] into cells↑→H+ leaves cells to blood for countering K+ into the cell→ [plasma H+]↑→ acidemia. • In an opposite manner, [ K+]o↓ (hypokalemia) →alkalemia. • [plasma H+]↑(acidemia)→K+ leave cells into blood→ [ plasma K+]↑(hyperkalemia). • In an opposite manner, [plasma H+]↓(alkalemia) → hypokalemia. • Plasma K+ levels at the time of onset of either acidemia or alkalemia affect the ability of the kidney to compensate for the acid-base disturbance. Renal handling of calcium and phosphate Renal handing of calcium • All segments of the nephron reabsorb calcium except the descending limb of the loop of Henle. • Calcium moves from the tubular fluid into the epithelial cells by passive diffusion down a concentration gradient. On the basal lateral side of the cells, it leaves either in exchange for Na ions or by means of an ATP-requiring calcium efflux pump. • Reabsorption is influenced by parathyroid hormone (PTH) and calcium levels. • An increase in plasma calcium levels reduces Ca++ reabsorption , while an increase in PTH results in an increase in Ca++ reabsorption. Renal handling of calcium and phosphate Renal Handling of Phosphate • Phosphate is reabsobed in the proximal tubule coupled with sodium reabsorption. • Phosphate reabsorption exhibits saturation. • The maximum capacity of this reabsorptive system is close to the amount of phosphate normally filtered. • Parathyroid hormone (PTH) inhibits renal phosphate reabsorption. PTH lowers the transport maximum of the Naphosphate co-transporter, reducing phosphate reabsorption and increasing phosphate excretion. IX. Micturition Urinary excretion Urinary excretion is the renal important function for maintaining normal metabolism and homeostasis of internal environment in the human body. Urinary excretion Pr es su re in th e Bl ad de r( c m H2 O ) Bladder Contractive Wave Volume (mL) Volume and Pressure Relationship Curve in the Bladder Urinary excretion Pr es su re in th e Bl ad de r( c m H2 O ) Volume (mL) Volume and Pressure Relationship Curve in the Bladder Reflex of urinary excretion Reflex of urinary excretion Clinic Problem is related to Reflex of Urinary excretion Summary on renal physiology Consideration after class 1. Please describe the uropoietic elementary process . 2. What are the influential factors of glomerular filtration? 3. Please describe main position , patterns and mechanism of Na+ reabsorption. 4. Please describe physiological function and secretion regulation of ADH. 5. Please describe physiological function and secretion regulation of aldosterone. 6. What is the mechanism of water diuresis?