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بسم هللا الرحمن الرحيم ﴿و ما أوتيتم من العلم إال قليال﴾ صدق هللا العظيم االسراء اية 58 By Dr. Abdel Aziz M. Hussein Lecturer of Medical Physiology 1. Glucose, amino acids, vitamins, protein → 100% 2. HCO3- → 90% 3. inorganic phosphate → 80% 4. Na+ & water → 2/3 or 65% 5. K+, Ca2+, Mg2+ & urea → Variable amount Reabsorption Organic solutes as PAH, drugs, various amines and ammonia. Secretion a) Reabsorption of: 1. All filtered glucose, amino acids, vitamins, protein and Kreb’s cycle intermediates. 2. About 2/3 of filtered load of Na+ & water. 3. About 90% of the filtered load of HCO3- . 4. About 80% of the filtered inorganic phosphate. 5. Variable amount of K+, Ca2+, Mg2+ & urea. b) Secretion of • Organic solutes as PAH, drugs, various amines and ammonia. Descending LH: Starts: • At junction ( ) outer and inner strips of outer medulla Epithelium: 1. Very thin endothelial –like cells. 2. Few microvilli 3. Few mitochondria 4. Permeability (high to water, hard to solutes) Outer Strip Inner Strip Ascending LH: Thin ALH: • Presents only in long loops Epithelium: 1. Similar to DLH 2. Permeability • Impermeable to water • Permeable to solutes → allow Na reabsorption, and Urea secretion 1120 = NaCl 80 = Urea 600 = NaCl 600 = Urea Ascending LH: Thick ALH: Epithelium: 1. 2. 3. 4. 5. Tall epithelium Numerous microvilli Much mitochondria Basolateral border rich in Na-K pump Apical border contain Na-K-Cl2 transporter Apical border Basolateral border Tight Junctions Hypotonic fluid TEPD + 5 to +15 mv Na, Ca, Mg + + + 150- 200 mosm/L 30% Ca 65% Mg 10 % K 25% Na (6000-900 meq/day) 15% Water Urea • a) Distal convoluted tubule (early distal tubules • b) Connecting tubules (late distal tubule) • c) Collecting ducts DCT CT CD 1. 2. 3. 4. 5. Final adjustment of urine formation. Reabsorption of 7-10% of filtered load of Na+. Reabsorption of 10-15% of filtered lead of water. Secretion of variable amount of H+ & K+. Major control site for Na+, K+, Ca2+ & acid-base balance of body. • Many of these functions are controlled by hormones. 1. Represent early 2/3 of distal tubules. 2. Reabsorbs 4% of filtered load of Na+. 3. NaCl is transported by a Na+ - Cl- transporter located at apical border. 4. This transporter is inhibited by thiazide diuretics. 5. The basolateral Na+- K+ ATPase together with that of thick ALH has highest activity of any nephron segment. 6. The osmolarity of tubular fluid leaving DCT is 100 mOsm/L (i.e. more hypotonic) so, the diluting segments of the nephron are: thick ALH and early DCT. • It is the late 1/3 of distal tubules. • As the collecting duct, its cell types are principal and intercalated cells. • Has variable water permeability according to ADH level. • Its TEPD is negative (about -45 mV). • Important site for final adjustment of urine volume, reaction (pH) and composition. • Include: cortical (CCD), outer medullary (MCD) & inner medullary (papillary) (PCD). • Have 2 major cell types: • 1. Principal cells. • 2. Intercalated cells. CCD MCD PCD Proximal segment Distal segment The main site of reabsorption of No reabsorption of nutritional nutritional substances substances Reabsorption of large quantities Less absorption and smaller of salt & water capacity: 9% of filtered NaCl & 17% Transport of salt and water occurs Steep gradient in early distal tubule along small gradient so, fluid and the fluid leaving collecting leaving PT is isotonic. duct is usually hypertonic. Na+ concentration in urine is Na+ concentration in urine can be about 140 meq/L as plasma. as low as 1 meq/L. Leaky tight junction. Tight tight junction between the epithelial cells causing the steep gradient. pH 6.9 pH as low as 4.6 Na+ reabsorption is coupled to Na+ and water reabsorption are water. uncoupled. Not affected by aldosterone & Affected by Aldosterone & ADH. ADH. General characters 1. About 2/3 (67%) of the filtered Na+ with the same percentage of water i.e. iso-osmotic reabsorp. 2. TFNa / PNa ratio at the end of PT is one as it is isoosmotic 3. In early PT, Na+, water, glucose, HCO3, amino acids and organic anions as lactate, pyruvate, and phosphate …. all are absorbed 2ry to Na+. 4. In the late PT: Na+ is absorbed with chloride mainly. Paracellular Transport Transcellular Transport •Occurs mostly at early segment of PT a) Carrier –mediated transport Symport Na-K pump Antiport b) Channel –mediated transport Na Channels Na-K pump Na-K pump Electrogenic symport Electoneutral symport Na-K pump Electoneutral antiport Cl ions Na-K pump Na channels •Occurs mostly at late segment of PT a) Cl- derived Na Reabsorp. Early PT HCO3Cl = 105 meq/L Cl = 132 meq/L Na+ - Late PT a) Solvent drag Reabsorp. 3-5 mosmol/L PTC Water NaCl • % : 100% of glucose is reabsorbed in PT 2ry active transport Na-K ATPase Facilitated diffusion • This process is saturable and rate limited, due to saturation of the carrier, and it has a Tm. • The excess filtered glucose is excreted in urine as in DM. • Also; phlorizin competes with glucose for this transporter, thereby inhibiting glucose reabsorption • Galactose can compete with glucose at the luminal border, so increase plasma glucose as in pregnancy glucose appears in urine • Amino acids e.g. glutamate and glycine are absorbed Na-dependent 2ry active transport • The transport is limited due to saturation of the carrier • Proteins are reabsorbed after digestion by brush border enzymes into amino acids or they may be absorbed by endocytosis • This process is easily saturated, so large leakage of proteins in glomeruli → proteinuria • They are absorbed by Na-dependent 2ry active transport. • There are 2 transport systems; 1. One for monocarboxylates as lactate, pyruvate. 2. Other for di-carboxylates as malate, succinate and for tri-carboxylates as citrate. • As PAH, oxalate, urate, creatinine and drugs as penicillin and aspirin. • Secretion occurs by a Tm-limited process using transporters with low specificity (i.e. some anions and cations compete with each others for same transport system). Primary Secondary Tertiary • About 25% of the filtered load of Na+ • Is actively reabsorbed by a common transporter for Na+ - k+ - 2Cl-. • This transporter is inhibited by the loop diuretics as frusemide and edecrine. • This process plays a key role in counter current multiplier system, responsible for medullary gradient. Hypotonic CT and CDs reabsorb about 8% of the filtered load of Na+. • • • • 4% of filtered Na+ By common carrier with Cl-. Is inhibited by thiazide diuretics. Is impermeable to water, and the fluid leaving it is more hypotonic • So, thick ALH and early distal tubules are called the diluting segments of the nephron. • Types of cells; 1. Principle cell: a. Reabsorbs Na+ via special channels. • Is influenced by aldosterone (2% filtered Na ) b. Reabsorbs water (under control of ADH). c. Secrete K+: • K+ secretion is influenced by aldosterone hormone . • Na+ is actively reabsorbed by the principal cell of the CT and cortical CD mainly and to less extent by the outer MCD • Na+ diffuses passively from tubular fluid into the cell via apical epithelial Na+ channel (blocked by amiloride diuretics) • It is actively pumped through the basolateral side, to the interstitium by Na+ - K+ ATPase. • K+ enters the cell by the basolateral Na+ - K+ ATPase • High intracellular K+ → exits the cell via a basolateral K+ channel to the interstitium (recycling) or secreted via apical K+ channels to tubular fluid. • K+ secretion by these segments is the primary determination of K+ secretion and excretion in urine; therefore regulating K+ balance • The absorption of Na+ across the apical border makes the TEPD –ve up to -45 mv • This help secretion of either K+ or H+ or reabsorption of Cl- to paracellular space. • Types of cells; 2. Intercalated cell : a. Secretion of H+ by either; • H+ ATPase • K+- H+ ATPase b. Reabsorb K+ Electrolyte balance Na homeostasis K homeostasis Water balance Regulation of water output pH regulation Reabsorption of filtered HCO3 Secretion of H Distribution: Intracellular 98% concentration of 130 - 150 meq/L Extracellular 2% concentration of 130 150 meq/L. 1. Regulation of protein and glycogen synthesis. 2. Control of cell volume 3. Regulation of intracellular pH 4. RMP & action potential of neurons and muscles; thus affecting their excitability Input Output K intake K excretion by kidney Shift between ICF and ECF Shift of K between ICF and ECF • K+ is primary an intracellular cation • 80% of the ingested K+ is moved temporary ICF to prevent rapid elevation of ECF K+ concentration which is dangerous 1. Na+ - K+ ATPase activity. 2. H+ ion concentration 3. Body fluid osmolarity. 4. Vitality of the cell membrane a) Activators: insulin, β agonist, aldosterone, high K • These factors increase K shift into ICF → hypokalaemia b) Inhibitors: digitalis • These factors decrease K shift into ICF → hyperkalemia 1. Increase H+ exchange with intra cellular K+ K+ efflux hyperkalemia 2. Decrease H+ opposite effect hypokalemia Decrease ECF osmolarity shift of water ICF together with K+ hypokalemia. Increase ECF osmolarity shift of water ECF together with K+ hyperkalemia. Exercise and cell lysis K+ efflux hyperkalemia 1. At the PT: about 80% of the filtered K+ 2. At thick ALH: 10% of K+ 3. Connecting tubule and cortical collecting ducts where the actual K+ balance occurs: • K+ is secreted by the principle cells in amount ranging from 2% to 180% of the filtered K+. • K+ secretion occurs 2ry to Na+ reabsorption→ help increase of the electrochemical gradient for K+ secretion • High gradient for K secretion is; 1. high K+ concentration inside the cell 2. –ve lumen (TEPD is – 45mvolt). 1. Plasma K+ • Increase K+ concentration increase K+ secretion via: a. Activation of Na+ - K+ ATPase increase intracellular K+ b. Stimulation of aldosterone hormones. 2. Tubular flow rate: • Increase tubular flow rate increase K+ secretion via: a. Delivery of Na+ to the principle cell. b. Dilution of the secreted K+ 3) Acid - base status: • Acidosis decrease K+ secretion. • Alkalosis increase K+ secretion. 4) Aldosterone : • Aldosterone induced proteins (AIP) • So, the delay of action of aldosterone for 1-2 hours could be explained by the period necessary for the synthesis of AIP • The effectiveness of the kidney to control Na+ excretion is bitter than that for K+. • For example, in complete Na+ deprivation, only 0.01% of the filtered Na+ is excreted in urine while in complete deprivation of K+, 2% of the filtered K+ is secreted and excreted in urine and so, hypokalemia can develop. THANKS