Renal Physiology Lectures 5-7 PDF

Renal Physiology Lectures 5-7 Pawan Puri, DVM, PhD Associate Professor Department of Biomedical Sciences Tuskegee University College of Veterinary Medicine Tuskegee, AL  Tubular Reabsorption- Objectives Explain reabsorptio...

Renal Physiology Lectures 5-7 Pawan Puri, DVM, PhD Associate Professor Department of Biomedical Sciences Tuskegee University College of Veterinary Medicine Tuskegee, AL  Tubular Reabsorption- Objectives Explain reabsorption of sodium and the function of Na/K ATPase Describe the mechanism of reabsorption of water, urea and chloride in the proximal tubule Explain reabsorption of peptides and small molecular weight proteins in the proximal tubules Clinical Correlation-Proteinuria  Trans-epithelial transport Step 1: The substance must leave the tubular fluid by crossing the luminal membrane. Step 2 Must pass through the cytosol from one side of tubular cell to another. Step 3: It must cross the basolateral membrane of the tubular cell to enter the interstitial fluid. Step 4: It must diffuse through the interstitial fluid. 15-8a  Sodium reabsorption by the various parts of the nephron 65% of sodium is reabsorbed in the FR= Fractional Reabsorption proximal tubule, 25% in the loop of Henle FE= Fractional Excretion and 4-8% in the distal and collecting tubule. Sodium reabsorption in the proximal tubule plays a pivotal role in reabsorbing glucose, amino acids, H2O, Cl , and urea. Sodium reabsorption in the ascending limb of the loop of Henle, along with Cl reabsorption, plays a critical role in the kidneys’ ability to produce urine of varying concentrations and volumes, depending on the body’s need to conserve or eliminate H2O. Sodium reabsorption in the distal and collecting tubules is variable and subject to hormonal control. It plays a key role in regulating ECF volume, which is important in long-term control of arterial blood An active Na–K ATPase pump in the basolateral membrane is essential for Na reabsorption. 80% of the total energy spent by the kidney is spent on running the Na/K ATPase pump. Na–K pump actively extrudes Na from the cell and builds up the concentration of Na in the lateral space. Intracellular Na concentration becomes low. A concentration gradient is established that favors the passive movement of Na from its higher concentration in the tubular lumen across the luminal border into the tubular cell. Sodium continues to diffuse down a concentration gradient from its high concentration in the lateral space  Active Na reabsorption is responsible for the passive reabsorption of H2O, Chloride and urea Water is passively reabsorbed through- out the length of the tubule as H2O osmotically follows Na that is actively reabsorbed. Of the H2O filtered, 65%—117 liters per day—is passively reabsorbed by the end of the proximal tubule. During reabsorption, H2O passes primarily through aquaporin 1 water channel. The return of filtered H2O to the plasma is enhanced by the fact that the plasma-colloid osmotic pressure is greater in the peritubular capillaries than elsewhere.  Active Na reabsorption is responsible for the passive reabsorption of urea and chloride Urea’s concentration as it is filtered at the glomerulus is identical to its concentration in the plasma entering the peritubular capillaries. Osmotically induced reabsorption of H2O in the proximal tubule secondary to active Na reabsorption produces a concentration gradient for urea that favors passive reabsorption of this waste. Because the walls of the proximal tubules are only somewhat permeable to urea, only about 50% of the filtered urea is passively reabsorbed by this means. Even though only half of the filtered urea is eliminated from the plasma with each pass through the nephrons, this removal rate is adequate.  Reabsorption of filtered peptides by the Proximal tubule Substances with a molecular weight of about 10 kDa are freely filtered at the glomerulus; as molecular weight increases from 10 kDa to 70 kDa, there is a roughly linear decline in the amount of solute filtered. The proximal tubule also reabsorbs filtered peptides and low– molecular-weight proteins. A large proportion of filtered peptides are degraded to amino acids by peptidases in the proximal tubule brush border and are reabsorbed by co-transport with Na+ across the apical plasma membrane Reabsorption of low molecular weight proteins by the Proximal tubule Low–molecular-weight filtered proteins such as insulin, glucagon and parathyroid hormone etc are taken up at the apical plasma membrane by receptor- mediated endocytosis. These proteins bind receptors (megalin (M) and cubilin (C) in the plasma membrane and undergo endocytosis. Endocytosed proteins are delivered to lysosomes and degraded Released amino acids  Clinical Correlation: Proteinuria https://fac.ksu.edu.sa/sites/default/files/3_quantitative_protein_estimation_of_urine.pdf  Objectives Reabsorption of glucose in the proximal tubule-Clinical Correlation Sodium and potassium handling at the LOH, DCT and collecting tubules Mechanism of action of aldosterone Potassium handling by different parts of the nephron Aldosterone- Clinical Correlation (Hypoadrenocorticism) Aldosterone antagonists- Spirolactone- Diuretics  Glucose is reabsorbed by Na- dependent secondary active transport in proximal tubules Glucose moves uphill against their concentration gradients from the tubular lumen into the blood until their concentration in the tubular fluid is virtually zero. Sodium and glucose co-transporter (SGLT), located only in the proximal tubule simultaneously transfer both Na and the specific organic molecule from the lumen into the cell. A limited number of SGLT molecules are present in the cells lining the tubules, there is an upper limit on how much glucose can be actively transported. This transport maximum is designated as the tubular maximum, or Tm. Any quantity of a substance filtered beyond Tm is not Mather & Pollock 2010  Mechanisms of sodium, chloride, and potassium transport in the thick ascending loop of Henle. The sodium-potassium ATPase pump in the basolateral cell membrane maintains a low intracellular sodium concentration and a negative electrical potential in the cell. The 1-sodium, 2-chloride, 1-potassium co-transporter in the luminal membrane transports these three ions from the tubular lumen into the cells, using the potential energy released by diffusion of sodium down an electrochemical gradient into the cells.  Mechanism of sodium chloride transport in the early distal tubule. The sodium-potassium ATPase pump in the basolateral cell membrane maintains a low intracellular sodium concentration. The sodium-chloride co- transporter moves sodium chloride from the tubular lumen into the cell. Chloride diffuses out of the cell into the renal inter­- stitial fluid through chloride channels in the basolateral membrane.  Diuretics- mechanisms of action Medical Physiology: Kibble  ACTIVATION OF THE RENIN– ANGIOTENSIN–ALDOSTERONE SYSTEM The granular cells themselves function as intrarenal baroreceptors. In response to a fall in NaCl, the macula densa cells trigger the granular cells to secrete more renin. Increased sympathetic activity stimulates the granular cells to secrete more renin. Regulation of Na reabsorption and Potassium ion secretion by aldosterone. Na/K ATPase pump moves Na out of the cell and transports K from the lateral space into the principal cells of CT. High intracellular K concentration favors net movement of K from the cells into the tubular lumen passively through the large number of K leak channels in this barrier in the distal and collecting tubules. K out of the peritubular capillary plasma into the interstitial fluid.  Mechanism of action of aldosterone to stimulate Na and Cl reabsorption Acute effects Chronic effects Aldosterone stimulates Increases Na+,K+-ATPase Na+,K+-ATPase activity. abundance. Aldosterone increases the Increases the apical open probability of the plasma membrane apical plasma membrane expression of the apical Na+ channels (ENaC), NaCl co-transporter (NCC) enhancing Na+ in the distal convoluted reabsorption. tubule. Increases the epithelial Na+ channel (ENaC) in collecting duct principal cells.  Summary of the Na handling by the kidney The kidneys adjust the amount of salt excreted by controlling two processes: 1) GFR 2) Na reabsorption The amount of Na filtered is controlled by regulating the GFR. The amount of salt filtered is adjusted as part of the general blood pressure regulating reflexes. Na reabsorption in the distal and collecting tubules is the powerful renin– angiotensin– aldosterone system (RAAS), Sodium Excreted = Sodium Filtered –Sodium which promotes Na reabsorbed reabsorption and thereby Na retention. Distribution of potassium in the body compartments 98% of the K is in the ICF, because the Na –K pump actively transports K into the cells. Because only a relatively small(2%) amount of K is in the ECF, even slight changes in the ECF K load can have a pronounced effect on the plasma K concentration. Potassium plays a key role in the membrane electrical activity of excitable tissues such as heart and muscle. Both hyperkalemia and hypokalemia result in decreased cardiac excitability handling by the kidney Potassium is actively reabsorbed in the proximal tubule, loop of Henle and in a specific type of intercalated cells in the kidney. Most K in the urine is derived from controlled K secretion in the distal parts of the nephron rather than from filtration. K is actively secreted by principal cells in the distal and collecting tubules. During K depletion, K secretion in the distal parts of the nephron is reduced to a minimum, so only the small percentage of filtered K that escapes reabsorption in the proximal tubule is excreted in the FR= Fractional Reabsorption urine. FE= Fractional Excretion When plasma K levels are elevated, K secretion is adjusted so that just enough K is added to the filltrate for elimination to  Several factors can alter the rate of K secretion, the most important being aldosterone. A rise in plasma K concentration directly stimulates the adrenal cortex to increase its output of aldosterone, which in turn promotes the secretion and ultimate urinary excretion and elimination of excess K. A decline in plasma K concentration causes a reduction in aldosterone secretion and a corresponding decrease in aldosterone-  Aldosterone functions in the kidney Aldosterone Principal cells of Intercalated cells of collecting ducts collecting ducts -Na reabsorption Stimulates hydrogen and retention in the secretion and body excretion -K secretion and excretion from the body Contributes to acid base balance Contributes to electrolyte and acid- base balance  Hypoadrenocorticism-Addison’s Disease Aldosterone Deficiency Hyperkalemia, Hyponatremia, hypochloremia, metabolic acidosis Polyuria, Polydipsia, Weakness, recurrent history of vomiting and diarrhea  Insufficient Aldosterone in Hypoadrenocorticism Principal Cells of Collecting Intercalated cells of ducts collecting ducts -Na reabsorption -K can not be can not occur, secreted leading to hydrogen ion can leading to Hyperkalemia not be secreted and Hyonatremia excreted Muscle Weakness, Loss of Medullary Cardiac arrhythmia Osmotic gradient Metabolic Acidosis Kidney can not concentrate urine leading to PU/PD, Dehydration, Spirolactone- Potassium Sparing Diuretic Spirolactone- Aldosterone antagonist Binds to aldosterone receptor and makes an inactive complex Blocks aldosterone mediated activation and expression of Na/K ATPase -Stimulates Na excretion from the body -K is retained the body Loss of water from the body Spirolactone- Potassium Sparing Diuretic Spirolactone- Aldosterone antagonist Binds to aldosterone receptor and makes an inactive complex Blocks aldosterone mediated activation and expression of Na/K ATPase -Stimulates Na excretion from the body -K is retained the body Loss of water from the body