Regulation of Renal Function PDF

Regulation of Renal Function Dr. Catherine McDermott Learning objectives This lecture aims to introduce and discuss the following: Regulation of GFR The Countercurrent Mechanism  Osmotic gradients in the kidney Regulation of urine concentration Lecture learning outcomes...

Regulation of Renal Function Dr. Catherine McDermott Learning objectives This lecture aims to introduce and discuss the following: Regulation of GFR The Countercurrent Mechanism  Osmotic gradients in the kidney Regulation of urine concentration Lecture learning outcomes After actively participating in this weeks lecture and completing additional tasks as indicated, you will be able to: Describe the intrinsic and extrinsic mechanisms involved in regulating GFR Explain the importance of the medullary osmotic gradient Describe how the medullary osmotic gradient is created Describe how the medullary osmotic gradient is maintained Describe in detail how anti diuretic hormone regulates urine concentration Glomerular Filtration Driven by blood pressure Net Filtration Pressure (NFP)  Glomerular hydrostatic pressure (BP)  Blood colloidal osmotic pressure  Capsular hydrostatic pressure Net filtration pressure  10 mmHg Glomerular Filtration Rate (GFR) The volume of filtrate formed each minute Directly proportional to NFP Adults – 120-125 ml/min Regulation of Glomerular Filtration  Renal autoregulation  Neural control Extrinsic Controls Sympathetic activity ↓ GFR by constricting renal arterioles Stress / emergency  Hormonal control Renin-angiotensin mechanism ↓ pressure leads to production of angiotensin II Constrict arterioles  Renal Autoregulation Myogenic mechanism  Smooth muscle contracts when stretched  Increased BP causes afferent arterioles to constrict  Restricting blood flow to glomerulus  Maintaining GFR Tubuloglomerular feedback mechanism  Macula densa of juxtaglomerular apparatus  Responds to filtrate [NaCl]  If GFR ↑, insufficient time for tubular reabsorption and NaCl remains high in the distal nephron  Macula densa release vasoconstrictors  Decreases NFP and GFR Intrinsic mechanisms cannot handle extremely low systemic BP Autoregulation ceases when MAP drops below 80 mmHg Tubuloglomerular Feedback 1. Increased GFR leads to increased NaCl in tubular fluid 2. ↑ uptake of NaCl across apical membrane of macula densa via Na+-K+-2Cl- symporter 3. Results in increased ATP and adenosine (ADO) 4. ATP binds P2X receptors and ADO binds A1 receptors in membrane of smooth muscle surrounding arteriole, causing increased [Ca 2+]i 5. Vasoconstriction of afferent arteriole 6. GFR decreased ATP and ADO also inhibit renin release by granular cells Sympathetic Control Volume of ECF normal  SNS at rest  Blood vessels dilated  Renal autoregulation prevails Stress/Emergency  Shunt blood to vital organs  Noradrenaline acts on α-adrenoceptors  Constricting afferent arterioles  Inhibition of filtrate formation  Also stimulates granular cells to release renin Glomerular Filtration Rate Regulation of Urine Concentration and Volume Osmolality  Number of solute particles particles dissolved in 1L of water  Reflects solution’s ability to cause osmosis  Body fluids measured in milliosmol (mOsm)  Kidneys keep body fluids constant at ~ 300mOsm By regulating urine concentration and volume The Nephron Juxtamedullary nephron  15% of nephrons  Arise in cortex-medullary junction  Important in producing concentrated urine  Loops of Henle deeply invade medulla  Regulation of Urine Concentration and Volume Achieved using countercurrent mechanism Fluid flows in opposite directions through adjacent segments of the same tube Establish a osmotic gradient from cortex to medulla Allows the kidneys to vary urine concentration in the collecting ducts (via ADH) Comprises:  Loop of Henle of juxtamedullary nephrons Countercurrent Multiplier  Vasa Recta Countercurrent Exchanger Countercurrent Multiplier Descending limb of Loop of Henle  Freely permeable to water  Impermeable to solutes Ascending limb of Loop of Henle  Impermeable to water  Permeable to solutes Tubular fluid becomes more concentrated as it moves down the Loop of Henle and then more dilute as it moves back up Interstitial fluid osmolality increases as you move down descending limb  Countercurrent Exchanger Vasa recta  Maintain osmotic gradient established  While supplying medullary cells with nutrients  As blood flow into medulla it loses water and gains NaCl  As blood emerges from medulla in to cortex gains water and loses NaCl Purpose of Medullary Gradient Without this gradient it would be impossible to raise the concentration of urine above 300mOsm Controlled by ADH  Acts on collecting ducts  Inserts aquaporins into luminal membrane  Amount of ADH determines the number of aquaporins inserted and amount of water reabsorbed Regulation of Urine Concentration Water Balance To remain hydrated, water intake must equal water output  Water intake and output are closely regulated Water intake sources  ingested fluid (60%) and solid food (30%)  metabolic water (10%) Water output  Urine (60%) and feces (4%)  Insensible losses (28%), sweat (8%) Obligatory water losses (how much?):  Insensible water losses from lungs and skin  Water accompanying undigested food residues in feces  Urine solutes flushed out of the body in water Regulation of Water Balance: ADH Antidiuretic Hormone (ADH) / Vasopressin Produced by the hypothalamus Secreted from the posterior pituitary  ↑ osmolality of the body fluids  ↓ volume and pressure of the vascular system  Drugs, nicotine, alcohol, nausea, ANP and angiotensin II Increases permeability of collecting ducts to:  Water (primary action)  Urea Stimulates reabsorption of NaCl by thick ascending limb of Loop of Henle, DT and collecting duct Osmotic Control of ADH Secretion Most important regulator  ~1% change in osmolality can significantly alter ADH secretion  Osmoreceptor in the hypothalamus  ↑ plasma osmolality Receptor send signal to ADH synthesizing/secreting cells located in the supraoptic and paraventricular nuclei of the hypothalamus  ADH rapidly degraded in plasma Circulating levels reduced to zero rapidly once secretion is inhibited  Hemodynamic Control of ADH Secretion ↓ blood volume or pressure  Stimulates secretion of ADH Receptors  Left atrium and large pulmonary vessels  Aortic arch and carotid sinus  Signals carried in afferent fibres of vagus and glossopharyngeal nerves to the brain stem  Relayed to ADH-secreting cells of the supraoptic and paraventricular hypothalamic nuclei.  Less sensitive than osmoreceptors  5-10% blood volume/pressure required Changes in blood volume/pressure can affect response to changes in osmolality  Shift in set point  Actions of ADH on the Kidneys 1. ADH binds to V2 receptor in basolateral membrane 2. Action of associated G protein on adenylyl cyclase (AC) ↑ cAMP 3. cAMP activates protein kinase A 4. Resulting in insertion of vesicles containing activated aquaporin-2 (AQP2) into the apical membrane of the cell. Synthesis of AQP2 also ↑ 5. When ADH removed, AQP2 are reinternalized Basolateral membrane permeable to water due to the presence of AQP 3 and AQP4 References Human Anatomy and Physiology, 9th Edition by Marieb and Hoehen, Chapter 25, p. 955-977