Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

Menti: 859 4198 RENAL REGULATION OF WATER, IONS AND ELECTROLYTES By Amelia ShabirRENAL REGULATION OF WATER, IONS AND ELECTROLYTES TILOs: I. Urogential homeostatic mechanism: Summarise the mechanisms regulating ion/water balance and acid-base homeostasis under normal and pathological conditions.Renal Regulation – Water Water is reabsorbed at the following regions of the nephron: Location Reabsorption? Transporter PCT DCT H 2 PCT Passive Paracellular route Descending LOH Passive Aquaporins Ascending LOH Impermeable Descending LOH CT H O H2O 2 DCT Impermeable Ascending LOH Collecting duct Passive Aquaporins Water reabsorption is passive, and is driven by active reabsorption of ions and solutesNephron Mechanics The medullary interstitium is maintained at a hyper-osmotic state to allow for passive water reabsorption at the LOH 1. Counter-current Multiplication Thick ascending Active process which generates and maintains an osmotic gradient in the medullary interstitium LOH • At the thick ascending LOH, there is reabsorption H2O Descending Na , Cl (active) of ions into the medulla LOH • Concentration gradient is created → passive H 2 + Na , Cl Na movement of water into the medulla at the Cl Thin ascending Na+ descending LOH H2O - LOH Cl H O • Flow of new tubular fluid through the LOH moves 2+ - the hypertonic filtrate towards the deep medulla Na , Cl (passive) Nephron Mechanics The medullary interstitium is maintained at a hyper-osmotic state to allow for passive water reabsorption at the LOH 2. Urea Recycling UT-A1 UT-A3 Passive process which maintains hyperosmolarity of the medullary interstitium • At the CT, urea is passively reabsorbed into the Urea medulla • Once in the medullary interstitium, urea has 2 fates: UT-A2 1. Transported into the vasa recta 2. Reabsorbed into the descending LOH (recycling)Anti-Diuretic Hormone Anti-diuretic hormone (ADH) promotes water absorption by the kidney nephrons Mechanisms of Action Lumen Blood 1. Upregulates number of aquaporin channels at the CT H2O • Binds to V2 receptors on the epithelial cells of the CT → increases number of aquaporin-2 and aquaporin-3 channels AQP-2 AQP-3 on epithelial cells of the CT 2. Promotes Na reabsorption at the LOH, DCT and CT , which drives passive water reabsorption Location Transporter Thick ascending LOH Na -K -2Cl symporters DCT Na -Cl symporters ↑ ADH upregulates the number of these transporters + Collecting duct Na channels Menti: 859 4198 Anti-Diuretic Hormone Anti-diuretic hormone (ADH) promotes water absorption by the kidney nephrons • ADH is produced by the hypothalamus and stored in the posterior pituitary gland Stimulatory Inhibitory Signs of ↑ Plasma osmolarity ↓ Plasma osmolarity Signs of hypovolemia hypervolemia ↓ Blood pressure ↑ Blood pressure Angiotensin II Atrial natriuretic peptide (ANP) Nicotine Ethanol Increased reabsorption of H2O Decreased reabsorption of H 2 Production of hyper-osmolar Production of hypo-osmolar Effect on urine production? urine and reduction in urine urine and increase in urine volume volume Menti: 859 4198 Disorders of ADH Insufficient ADH Excessive ADH Diabetes insipidus (a.k.a. arginine vasopressin Symptom of Inappropriate ADH secretion (SIADH) deficiency): causes increased, dysregulated ADH • AVP deficiency is caused by impaired production production of ADH Clinical presentation: • AVP resistance is caused by decreased ADH • Hyponatremia response in the kidneys • Low-volume, hyperosmolar urine Clinical presentation: • Polyuria • Polydypsia + - Renal Regulation – H & HCO 3 + - H 2 + CO ⇋ H 2O ⇌ H 2 HCO3 3 1. Reabsorption of HCO - 3 2. Generation of (new) - Regulated by Regulated by HCO 3 3. Secretion of H+ respiratory system kidneys HCO Reabsorption 3 • HCO is r3absorbed at the PCT + + Na -H Na -HCO 3 antiporter symporter + - + H HCO 3 H ATPase Lumen Blood + - Renal Regulation – H & HCO 3 HCO Re3bsorption - • HCO is 3eabsorbed at the DCT and CT by ɑ-intercalated cells Lumen Blood Lumen Blood + + H -K ATPase Cl -HCO3- - - antiporter Cl -HCO 3 + antiporter H ATPase H + HCO 3- HCO - H + H ATPase 3 ɑ-intercalated cells β-intercalated cells Urine becomes more Acidic Urine becomes more Basic + - Renal Regulation – H & HCO 3 - Generation of (new) HCO 3 - • HCO is 3enerated at the PCT, DCT and CT through 2 main mechanisms: 1. Excretion of NH + 4 • Occurs at the PCT Lumen Blood • Glutamine enters tubular epithelial cells Glutamine Na -H+ via diffusion antiporter 2 x NH 4+ A2- • Deamination results in formation of 2 x NH 4+ and ɑ-ketoglutarate ion A 2- NH3 2 x HCO 3- • A is converted into 2 x HCO 3- molecules, which are reabsorbed + + + • NH 4 is excreted via Na -H antiporters or diffusion (if converted into NH ) 3 + - Renal Regulation – H & HCO 3 - Generation of (new) HCO 3 - • HCO is 3enerated at the PCT, DCT and CT through 2 main mechanisms: 2. Excretion of titratable acids • Occurs at the ɑ-intercalated cells of the Lumen Blood H -K ATPase DCT and CT Cl -HCO 3 antiporter • Utilises the phosphate buffer system: + H + HCO 3- H PO ⇌ H + H PO 2- H ATPase 2 4 2 4 Neutralizes H generated from carbonic acid - • H PO2is e4creted via urine + Renal Regulation – Na Na is reabsorbed at the following regions of the nephron: Location Reabsorption? Transporter PCT DCT + Na+ Na PCT Active Various Descending LOH Impermeable Thin ascending + Descending LOH Passive Na channels LOH CT Thick ascending Na -K -2Cl- Na+ Active LOH symporters Ascending DCT Active Na -Cl symporters LOH Na+ Collecting duct Passive Na channels + Regulation of Na Intake Intake of Na is regulated at both the central and peripheral levels: Central Peripheral Regulated by lateral parabrachial nucleus in the Regulated by taste receptors on the tongue: brainstem: + • Low concentrations of dietary Na stimulates • In normal conditions, glutaminergic activity in appetite the nucleus inhibits Na cravings • Excessively high concentrations of dietary Na + • In hypovolemic conditions, GABA-nergic has an aversive effect activity in the nucleus increases Na cravingsAldosterone Aldosterone promotes Na absorption by the kidney nephrons • Produced in the zona glomerulosa of the adrenal glands Mechanisms of Action MR protein 1. Upregulates Na reabsorption at the DCT and Hsp90 CT • Binds to mineralocorticoid receptors Lumen Blood (MR) in tubular epithelial cells • Dissociation of chaperone heat shock Activated MR dimer protein 90 (Hsp90) from MR proteins • Activated MR protein dimers upregulate the Na channels Na -K ATPase + expression of Na channels and Na -K + + Na ATPaseRAAS The renin-angiotensin-aldosterone system (RAAS) regulates production of aldosterone Angiotensin Adenosine Renin released by released by juxtaglomerular macula densa mesangial cells Angiotensin I Angiotensin-converting Enzyme (ACE) Aldosterone produced Systemic by adrenal glands vasoconstriction Angiotensin IIRAAS The renin-angiotensin-aldosterone system (RAAS) regulates production of aldosterone Stimulatory Inhibitory ↑ Sympathetic activity ↓ Sympathetic activity ↓ Na in renal tubules ↑ Na in renal tubules ↓ ANP ↑ ANP Increased production of Decreased production of angiotensin II and aldosterone angiotensin II and aldosterone Increased Na and H O 2 Decreased Na and H O 2 reabsorption, increase in BP reabsorption, decrease in BP Menti: 859 4198 Disorders of Aldosterone Hypoaldosteronism Hyperaldosteronism Insufficient aldosterone production leads to Excessive aldosterone production leads to + + decreased Na (and H O)2reabsorption excessive Na (and H O2 reabsorption Clinical presentation: Clinical presentation: • Hypotension • Hypertension • Palpitations • Muscle weakness • Salt cravings • Thirst • Polyuria Liddle’s disease is a genetic disorder characterised by gain-of-function mutations in Na⁺ channels • Excessive, dysregulated Na reabsorption leads to hypertension despite suppressed aldosterone productionRegulation of Volume Baroreceptors detect changes in blood pressure High-pressure Low-pressure Carotid sinus Atria Aortic arch Right ventricle Release of renin Juxta-glomerular apparatus Pulmonary vasculature Hypovolemia (i.e. decrease in blood pressure) causes reduced baroreceptor firing: • Increased renin production • Increased ADH production • Increased sympathetic activityRegulation of Volume Baroreceptors detect changes in blood pressure High-pressure Low-pressure Carotid sinus Atria Release of ANP Aortic arch Right ventricle Juxta-glomerular apparatus Pulmonary vasculature Hypervolemia (i.e. increase in blood pressure) causes increased baroreceptor firing: • Increased ANP production • Decreased ADH production • Decreased sympathetic activityAtrial Natriuretic Peptide Atrial natriuretic peptide (ANP) decreases blood pressure and volume • Produced by atrial myocytes in response to atrial stretch Mechanisms of Action 1. Vasodilation of systemic and renal vessels 2. Inhibition of RAAS system • ↓ Renin production • ↓ Aldosterone production → decreased Na⁺ reabsorption at DCT and CT 3. Inhibition of Na⁺ reabsorption at PCT and CT + Renal Regulation – K + K is handled at the following regions of the nephron: Location Reabsorption? Transporter PCT DCT + K secretion K PCT Active Paracellular Descending LOH Impermeable Thin ascending Descending Passive CT LOH LOH + + + - K secretion Thick ascending Active Na -K -2Cl LOH symporters Ascending DCT Secretion K channels LOH K+ + Collecting duct Secretion K channels + Renal Regulation – K K is secreted by principal cells in the DCT and CT + + + Na -K K channels ATPase K+ + K Na channels + Na + K + K Lumen Blood Factors stimulating K secretion include: • Increased serum K + • Increasedaldosterone o Aldosterone increases Na reabsorption by increasing number of Na -K ATPase → increased+ + K entry into tubular epithelial cells + Renal Regulation – K + Factors stimulating K secretion: + • Increased serum K • Increasedaldosterone K channels Na -K ATPase K + • Increased insulin and plasma pH Na + o Increased activity of Na -H exchangers + → increased Na entry into tubular cells H + + Na -H exchangers o Increased Na entry stimulates activity of Na -K ATPase → increased K entry into Lumen Blood tubular cells • Increased tubular flow rate o Stimulation of cilia causes activation of PDK-1 channels → increased Ca 2+ reabsorption into tubular cells o Ca 2+increases activity (openness) of K⁺ channelsRenal Regulation – K + + Factors stimulating K secretion: • Increased serum K + • Increasedaldosterone • Increased insulin and plasma pH o Increased activity of Na -H exchangers + → increased Na entry into tubular cells o Increased Na entry stimulates activity of + - + Na -K ATPase → increased K entry into tubular cells • Increased tubular flow rate o Stimulation of cilia causes activation of PDK-1 channels → increased Ca 2+reabsorption into tubular cells o Ca 2+increases activity (openness) of K⁺ channels Menti: 859 4198 + Disorders of K Balance Hypokalemia Hyperkalemia • Inadequate dietary intake • ACE inhibitors • Diuretics • CKD • Fluid loss e.g. vomiting, diarrhoea Gitelman’s syndrome is a genetic disorder characterised by loss-of-function mutations in - apical Na⁺-Cl channels in the DCT • Insufficient Na reabsorption leads to increased activation of the RAAS → increased renin and aldosterone secretion → increased K + secretion What are some causes of hyperkalemia?Diuretics Class Site Mechanism of Action Side Effects Non-reabsorbable solute which increases osmolarity Osmotic PCT of filtrate Drugs in this class: Mannitol Class Mechanism of Action Side Effects Carbonic Inhibition of carbonic anhydrase in tubular epithelial anhydrase PCT cells → ↓ Na⁺ reabsorption due to ↓ activity of Na⁺-H⁺• Metabolic acidosis inhibitors antiportersDiuretics Class Site Mechanism of Action Side Effects Inhibition of Na⁺-K⁺-2Cl⁻ symporters → ↓ Na⁺ • Hyponatremia Loop LOH • Hypokalemia reabsorption • Hypotension Drugs in this class: Bumetanide, FurosemideDiuretics Class Site Mechanism of Action Side Effects Inhibition of Na⁺-Cl⁻ symporters on apical membrane• Hyponatremia Thiazide DCT → ↓ Na⁺ reabsorption • Hypokalemia Increases calcium reabsorption • Hypotension Drugs in this class: Indapamide, Hydrochlorothiazide Class Site Mechanism of Action Side Effects Mineralocorticoid receptor antagonists → • Hyperkalemia K -sparing DCT, CT competitive inhibitor of aldosterone • Gynaecomastia Drugs in this class: Spironolactone, EplerenoneTHANK YOU Contact Feedback as2322@ic.ac.uk