BIO5004A 2 Urine Production 2024 PDF

Human physiology BIO- 5004A/ BIO- 5104 Renal physiology II: Urine production. Solute & water transport along the nephron Dr Tracey Swingler  Human physiology BIO- 5004A/ BIO- 5104 Lectures L...

Human physiology BIO- 5004A/ BIO- 5104 Renal physiology II: Urine production. Solute & water transport along the nephron Dr Tracey Swingler  Human physiology BIO- 5004A/ BIO- 5104 Lectures Lecture 1: Introduction to the kidney Overview and glomerular filtration Lecture 2: Urine production Lecture 3: Regulation of ion and water balanc Dr Tracey Swingler  Human physiology BIO- 5004A/ BIO- 5104 Learning outcomes Understand the role of the different segments of the nephron Describe the process of reabsorption and secretion across the renal epithelial membranes Describe how and why the loop of Henle produces a hyperosmotic medulla Dr Tracey swingler Nephron: Overview Nephron Basic functional unit Filtration of blood nephrons: ~1 million Highly organised structure Cortical nephrons Short loop of Henle Juxtamedullary nephrons ~15% of all nephrons long loop of Henle‘s Generate osmotic gradient (Medulla) Very close Blood vessels proximity Transport in/out Vasa recta- reaborption of solutes JGA bule organisation: Cell types Single continuous tubule links Bowman‘s Epithelial cells capsule to the collecting duct ⁻ Tubule- One epithelial cell layer ⁻ 16 highly specialized epithelial cell types in the kidney ⁻ Podocytes (glomerular epithelial cell)- Filtration ⁻ Brush boarder cells for absorption in Proximal tubule ⁻ Cells that express different channels and transporters Structural and functional Regional segmentation differences in functions ⁻ Proximal convoluted tubule ⁻ Descending part of Henle‘s loop ⁻ Ascending part of Henle‘s loop Lots of ⁻ Distal convoluted mitochondria in ⁻ Collecting duct very active cells e nephron: Three basic processes The renal corpuscle The nephron: structural and functional unit Reabsorption Secretion Each segment performs specific Filtration transport functions 1.Filtration 2.Reabsorption 3.Secretion Waste elimination, balance water Excretion volume/ pH/ osmolarity In the process, this creates urine omerular filtration Ultra-filtration 300mOsm/L Glomerular filtration membrane 300mOsm/L Filtrate contains no blood cells/ proteins. Does contain water, glucose, amino acids, ions etc. chemically similar to serum GFR kept constant despite changes in BP Regulated by: 1. Intrinsic: Myogenic, Tubuloglomerular feedback (JGA) 2. Extrinsic: Hormonal and nervous control ubule organisation FILTRATION Lecture 1 REABSORTION SECRETION Filtrate Urine Transport of water: (Osmosis/ sometimes aquaporins) ⁻ Direction depends on the osmotic gradient Transport of solutes: (diffusion/ active transport) ⁻ Ion channels ⁻ Solute-specific transporters CONCENTRATION OF FILTRATE Reabsorption and secretion Movement of water and solutes across membranes ubular reabsorption DISTAL TUBULE & PROXIMAL TUBULE COLLECTING DUCT PCT reabsorbs ~ 65 % of the filtrate, Na : 65% Na : 10% H2O : 67% H2O : 17% absorbs a greater variety of chemicals (Fine tuning/Control) than any other part for the nephron, K+, Cl-, HCO3-, PCT: increased length of the tubule- surface area Cells contain abundant, large mitochondria- energy for active transport 6% of daily calories needed for processes in the PCT HENLE‘S LOOP Na : 25% High water permeability across the H2O : 15% epithelial cell layer Sodium reabsorption drives complete reabsorption of glucose and amino acids HCO3- and P mary of transport processes in renal tubules Filtration Reabsorption Secretion bular reabsorption Filtered loads are large, generally more than in the body, (body contains 40L of water) Substance Amount filtered per dayAmount excreted per day Percentage reabsorbed Water (L) 180 1.8 99 Sodium (g) 630 3.2 99.5 Glucose (g) 180 0 100 Urea (g) 54 30 44 Useful plasma Large fraction of components such as waste products are water, inorganic ions, excreted nutrients are reabsorbed ement of water across membranes Obligatory water Water can move between reabsorption cells( Paracellular) and through cells (cellular) AQUAPORINS are channel proteins which facilitate the passive diffusion of water across biological membranes ⁻ Increased rate of water transport across membranes ⁻ Driven by osmotic differences Because the water transport capacity of aquaporins is low, membranes often contain a high density of aquaporins, up to 10,000 per square micron, to increase water permeability ement of water across membranes: AQP 13 AQUAPORIN (AQP) channel isoforms in human AQP1 is extremely abundant in the PCT and descending loop of Henle - essential for urinary concentration. AQP2 is exclusively expressed in the principal cells of the connecting tubule and collecting duct and is the predominant ADH-regulated water channel. Water moves by OSMOSIS ment of water across membranes: Tight junctions Water can move through tight junctions Tight junctions are boundaries between apical and basolateral membranes Create a barrier to the flow of movement of solutes to and from the tubular fluid CLAUDINS are transmembrane proteins that form tight junctions Extracellular domain fir like zipper teeth and direct the ‘leakiness’ or tightness of the membrane H 2O Water moves by OSMOSIS PCT- leaky junctions DCT- tighter junctions ‘Solvent drag’ can carry some small ement of solutes across membranes Plasma membranes are NOT very permeable to most ions 2a. Active transport 1. Ions: Ion channels Na+ ⁻ Dependent on ion gradients across membranes ⁻ Diffusion down concentration gradient ATP ⁻ Ion specific K+ 2. Transporters: Specific transport of solutes Na+ Na+ against gradient a. Primary active transport- Chemical energy needed (ATP) to move against a gradient Na+ H 2O b. Secondary active transport of solutes Energy provided by ion gradient Osmosis 1. Diffusion 2b. Secondary 1. Symporter: Co-transport in the same direction active transport 2. Antiporter: Co-transport in opposite directions ment of solutes across membranes: Ion channels Na- K-ATPase Na- H antiporter The cells of the kidney contain many specialized ion channels and transporters Regulate VOLUME and IONIC Na- Glucose CONCENTRATION by absorption or secretion of co- ions into the urine transporter Each region of the kidney expresses a particular subset of ion channels to ensure electrolyte homeostasis bular reabsorption: Sodium Sodium is the most abundant cation in the Peritubular capillary filtrate Na+ Na+ reabsorption is key to reabsorption of Active Na+ other solutes transp Na + ort ATP 1. Simple diffusion through ion channel K+ Na+ 2. Active transport- ATPase Simple Na + 3. Water moves by osmosis diffusi on Na+ H2 O Na+ Na+ Na+ Na + Na+ Na + FILTRATE Tubular lumen ular reabsorption: Sodium and glucose Glucose plasma concentration X GFR (125ml/min) 1mg/ml Glucose filtered load is: 1mg/ml x 125ml/min= 125mg/min 1mg/ml PCT reabsorbs 99.9% filtered glucose Trace amounts excreted in urine ular reabsorption: Sodium and glucose Sodium-glucose co-transporter Peritubular capillary Form of secondary active transport Na+ Active Na+ 1. Simple diffusion of sodium through co- transp Na transporter + ort ATP 2. Active transport of sodium- ATPase GLUT1/2 K+ Na+ 3. Secondary active transport ⁻ Moves with sodium throum SGLUT Na+ ⁻ Glucose passive diffuses through GLUT1/2 Na+ Na+ into interstitial fluid and reabsorbed into diffusi bloodstream Na+ on H2 O Na + Na+ Na+ Na reabsorption is key to reabsorption of other Na + SGLUT Na+ + Na+ solutes Na FILTRATE Tubular lumen ular reabsorption: Sodium and amino acids Peritubular capillary Na+ Amino acids freely filtered across glomerular Near complete reabsorption of filtered amino Active Na + acids in PCT transp Na + ort ATP Different transport proteins for different amino acids K+ Na+ Na+ Transport across apical membrane occurs via Na+ Na+ symporters Na+ diffusi Na+ on H2 O Na + Na+ Na+ Na+ Na + Na+ Na + FILTRATE Tubular lumen ubular secretion SECRETION is a way to improve the efficiency of waste removal- moves non- Metabolic waste H+ HCO3- filtered substances into the tubule to be Drugs/ toxins excreted in urine Only 20% of the blood is filtered in the glomerulus every minute, so this provides an alternative route for substances to enter the tubular lumen. The PCT secretes: 1. Organic acids and bases eg bile salts, oxalate and catecholamines (waste products of metabolism) 2. Hydrogen ions- important in maintaining acid/ base balance in the body H+ secretion allows reabsorption of bicarbonate via carbonic anhydrase enzyme, 85% filtered bicarbonate is reabsorbed 3. Drugs/toxins –via the H+ exchanger on the Loop of Henle: Reabsorption of Water and sodium Maintenance of hyperosmotic medulla oop of Henle The primary function of the loop of Henle: generate an osmotic gradient that enables the collecting duct to concentrate urine and conserve water The Loop of Henle has a hairpin configuration with a thin descending limb and both, a thin and thick ascending limb The thin descending and ascending segments have thin, squamous epithelial membranes ⁻ minimal metabolic activity. Na+ ⁻ lots of aquaporins, very permeable to water ⁻ Impermeable to sodium H2O The thick has cuboidal epithelial membranes and is quite metabolically active. unter current multiplier Plasma The loop of Henle maintains hypertonic 300mOsM/ L conditions in the medulla 20 10 The descending loop of Henle permeable to 0 0 30 water but impermeable to salt ions. 0 The ascending loop of Henle is permeable to salt ions but impermeable water. Na+ ions are pumped out of the ascending limb into the interstitial fluid of the medulla Water flows out of the filtrate into the interstitial fluid of the medulla by osmosis following the concentration gradient absorbed into the blood stream Filtrate 1200 Medulla 1200mOsm/L Counter current because the flow of the filtrate in mOsM/L the descending and ascending loop is in opposite directions. unter current multiplier Cortex Allows the kidneys to reabsorb 300mOsm/L 10 around 99% of filtered water 0 Water leaves by osmosis from the collecting duct following stimulation by ADH As well as counter current multiplication, 400 40 Na+ 40 urea recycling helps reabsorb water 0 Na+ 0 60 60 600 H2 O 0 Na+ 0 80 H2 O 80 800 Na+ 0 0 90 Na+ 90 900 0 0 1200 Medulla 1200 nter current multiplier: The vasa vecta 300mOsM/L 300mOsM/L Large volume of water leaving the tubule is picked up a carried away by the vasa recta 300 Q. Why doesn’t it also carry away the sodium and urea needed for the counter current system 300 400 The vasa recta blood flows in the opposite 400 direction on adjacent capillaries 600 Blood flowing down into medulla- water leaves by osmosis and sodium moves in down 600 its conc gradient Blood flowing up: water moves in by osmosis, sodium moves out 1200 1200mOsM/L Also, the kidney capillaries are low flow! rea recycling 1. Urea freely filtered at glomerulus 2. 50% reabsorbed by solvent drag with water 50% Urea 3. 60% urea secreted into Loop of Henle (Urea 110% Urea conc. High in medulla) 4. Ascending limb and DCT impermeable to 100%Urea urea and water, so conc. of urea stays the same 5. 70% reabsorbed in the collecting duct 6. 40 excreted Urea movement is through urea transporter 70% Urea reabsorbed Urea 60% About 40% of the osmolarity in the medulla is secreted due to UREA ADH can affect the number of urea 40% Urea 110% Urea excreted transporter in the collecting duct rea recycling 50% Urea 110% Urea 100%Urea Urea is secreted back into the loop of Henle Maintains a pool of urea in the medulla interstitial fl As well as counter current Urea multiplication, urea recycling helps maintain the osmotic gradient in the medulla and help reabsorb water 110% Urea 40% Urea  The distal convoluted tubule and collecting duct: Fine tuning The distal convoluted tubule and collecting duct Fluid arriving at the DCT still contains 20% of the water and ~7% of the solutes from the filtrate If we were to pass this a urine = 36L/ day The DCT and collecting duct still need to absorb alot of water Reabsorb variable amounts of water and salts regulated by several hormones:  Aldosterone  ADH  ANP  Parathyroid hormone The distal convoluted tubule and collecting duct: 2 types of cells Most areas are composed of homogenous epithelium The DCT and collecting duct contain two types of cells Principal cells Most abundant cell type Involved in water and salt balance Have receptors for aldosterone (increases Na/ K pump), ADH increases aquaporins Increases water reabsorption Intercalating cells (alpha and beta) Fewer in number Reabsorb K+ and secrete H+: Involved in acid base balance Alpha cells- secretes H+ and reabsorbs HCO3– managing acidosis Beta cells - ( transporters are on the opposite + Urine The renal corpuscle Reabsorption Secretion Filtration Excretion  Check your learning outcomes Understand the role of the different segments of the nephron Describe the process of reabsorption and secretion across the renal epithelial membranes Describe how and why the loop of Henle produces a hyperosmotic medulla Any Questions?