Solute & Water Tubular Lects PDF

Renal Physiology March 21-25, 2024 J. Mohan, PhD. Lecturer, Physiology Unit, Department of Pre-clinical Sciences Faculty of Medical Sciences, U.W.I., St Augustine. Room 104, Physiology Unit, [email protected] Mini - Quiz 1. The hospital lab reports that your patient’s renal creatinine cleara...

Renal Physiology March 21-25, 2024 J. Mohan, PhD. Lecturer, Physiology Unit, Department of Pre-clinical Sciences Faculty of Medical Sciences, U.W.I., St Augustine. Room 104, Physiology Unit, [email protected] Mini - Quiz 1. The hospital lab reports that your patient’s renal creatinine clearance is 120 g/day. This value is : A. normal B. significantly above normal C. Not an interpretable number as presented Mini - Quiz 1. The hospital lab reports that your patient’s renal creatinine clearance is 120 g/day. This value is : A. normal B. significantly above normal C. Not an interpretable number as presented C. Unit of clearance is mL / min or L / day. See definition of clearance. Renal Clearance Definition : the volume of plasma completely cleared of a substance (x) by the kidneys per unit time Cx = Ux X V _______________ Px ml/min Where : C = clearance (ml/min) [U] x = Urine concentration of substance x (mg/ml) [P] x = Plasma concentration of substance x (mg/ml) V = Urine flow rate per minute (ml/min) Mini - Quiz 2. In an experiment, a clamp around the renal artery is partially loosened to increase renal arterial pressure from a mean of 90 mm Hg to 130 mm Hg. How much do you predict RBF will change? a. b. c. d. 30% increase no change 5-10% increase 30% decrease Mini - Quiz 2. In an experiment, a clamp around the renal artery is partially loosened to increase renal arterial pressure from a mean of 90 mm Hg to 130 mm Hg. How much do you predict RBF will change? a. b. c. d. 44% increase no change 5-10% increase 44% decrease C. ABP  by ~ 44%, but autoregulation prevents the RBF from increasing in proportion. Autoregulation is not perfect so some increase will occur, but less than 44% Importance of Autoregulation many activities can change arterial blood pressure, so, we need mechanisms that maintain RBF & GFR relatively constant despite changes in arterial pressure if RBF & GFR  or  suddenly in proportion to changes in blood pressure  urinary excretion of water & solute would also change suddenly; if no corresponding intake  fluid & electrolyte imbalance autoregulation of RBF & GFR : – provides an effective means for uncoupling renal function from arterial pressure; thereby maintaining a relatively constant GFR – ensures that fluid and solute excretion remain fairly constant – protects the glomerular filtration membrane from damage by high BP Mini - Quiz 3. A hypothetical condition is noted to cause a decrease in GFR. Identify 4 possible actions of the drug that might decrease GFR. Mini - Quiz 3. A hypothetical condition is noted to cause a decrease in GFR. Identify 4 possible actions of the condition that might decrease GFR. 1. Increase the thickness of glomerular capillary membrane   Kf 2. Lower arterial pressure   PGC 3. Constrict the afferent arteriole   PGC 4. Dilate the efferent arteriole   PGC Dynamics of Ultrafiltration GFR = Kf x Net Filtration Pressure (NFP) GFR can be altered by changing Kf or by changing NFP (which depends on the sum of the Starling forces) In normal individuals, the GFR is physiologically regulated by alterations in PGC :  PGC   GFR  PGC   GFR such changes PGC are mediated mainly by changes in : – 1) arterial pressure (buffered by autoregulation of GFR) – 2) afferent arteriolar resistance – 3) efferent arteriolar resistance Renal Blood Flow Figure 32-21 Relationship between selective changes in the resistance of either the afferent arteriole or the efferent arteriole on RBF and GFR. Constriction of either the afferent or efferent arteriole increases resistance, and according to Equation 32-11 (Q = ΔP/R), an increase in resistance (R) decreases flow (Q) (i.e., RBF). Dilation of either the afferent or afferent arteriole increases flow (i.e., RBF). Constriction of the afferent arteriole (A) decreases PGC because less of the arterial pressure is transmitted to the glomerulus, thereby reducing GFR. In contrast, constriction of the efferent arteriole (B) elevates PGC and thus increases GFR. Dilation of the efferent arteriole (C) decreases PGC and thus decreases GFR. Dilation of the afferent arteriole (D) increases PGC because more of the arterial pressure is transmitted to the glomerulus, thereby increasing GFR. (Modified from Rose BD, Rennke KG: Renal Pathophysiology: The Essentials. Baltimore, Williams & Wilkins, 1994.) Figure 32. 21; Koeppen & Stanton, 2010 Today’s Topics Measurement of Reabsorption & Secretion Solute and water transport along the nephron – Renal handling of glucose – Early Proximal Tubule Reabsorption of Na+ coupled with glucose, amino acid, bicarbonate, phosphate, lactate & citrate – Late Proximal Tubule Reabsorption of NaCl – – – – – Isosmotic reabsorption in the PT Glomerulotubular Balance in the PT Loop of Henle Early Distal Tubule Late Distal Tubule & Collecting Duct Mechanisms of Urine Formation Urine formation and adjustment of blood composition involves three major processes – Glomerular filtration – Tubular reabsorption – Secretion Figure 25-9a; Marieb & Hoehn, 2010 Measurement of Reabsorption & Secretion Filtration : an interstitial-type fluid is filtered across the glomerular capillary into Bowman’s space Filtered Load : the amount of a substance filtered per unit time Figure 26-9; Hall, 2011 Basic kidney processes that determine the composition of the urine. Urinary excretion rate of a substance is equal to the rate at which the substance is filtered minus its reabsorption rate plus the rate at which it is secreted from the peritubular capillary blood into the tubules. Measurement of Reabsorption & Secretion Reabsorption : Water and Solutes (Na+, Cl-, HCO3-, glucose amino-acids, urea, Ca2+, Mg2+, phosphate, lactate, citrate) reabsorbed from glomerular filtrate into the peritubular capillary blood Reabsorption mechanism requires transporters in the membranes of renal tubule epithelial cells Figure 26-9; Hall, 2011 Measurement of Reabsorption & Secretion Secretion : Some substances (organic acids, organic bases, K+) are secreted from peritubular capillary blood into tubular fluid Secretion mechanism requires transporters in the membranes of renal tubule epithelial cells Figure 26-9; Hall, 2011 Measurement of Reabsorption & Secretion Excretion /Excretion rate : The amount of a substance excreted per unit time Sum of the processes of filtration, reabsorption & secretion Excretion rate can be compared to the filtered load to determine whether a substance has been reabsorbed or secreted Figure 26-9; Hall, 2011 Measurement of Reabsorption & Secretion Filtered Load of substance x = GFR x [ Px ] Excretion rate of substance x = [Ux] x V Reabsorption or Secretion Rate = Filtered Load - Excretion Rate Figure 26-9; Hall, 2011 Examples Figure 6-13; Costanzo, 2022 Mini - Quiz 1. Substance T is present in the urine. Does this prove that it entered the renal tubule only by filtration at the glomerulus? Mini - Quiz 1. Substance T is present in the urine. Does this prove that it entered the renal tubule only by filtration at the glomerulus? No. Substance T could have entered the renal tubule by filtration at the glomerulus or by secretion from the peritubular capillaries. Mini - Quiz 2. Substance V is NOT normally present in the urine. Does this mean that it does not enter the kidney at all via the renal artery or is neither filtered nor secreted? Mini - Quiz 2. Substance V is NOT normally present in the urine. Does this mean that it does not enter the kidney at all via the renal artery or is neither filtered nor secreted? It is possible that it was neither filtered nor secreted, but it is more likely that it is completely reabsorbed from the tubule into the blood. Today’s Topics Measurement of Reabsorption & Secretion Solute and water transport along the nephron – Renal handling of glucose – Early Proximal Tubule Reabsorption of Na+ coupled with glucose, amino acid, bicarbonate, phosphate, lactate & citrate – Late Proximal Tubule Reabsorption of NaCl – – – – – Isosmotic reabsorption in the PT Glomerulotubular Balance in the PT Loop of Henle Early Distal Tubule Late Distal Tubule & Collecting Duct Solute and Water Transport along the Nephron Filtered at the glomeruli : ~ 180 L/day of essentially proteinfree fluid BUT < 1% of the filtered H2O & NaCl, and variable amounts of other solutes are excreted in urine Table 33-1, Koeppen & Stanton, 2010 Solute and Water Transport along the Nephron reabsorption & secretion = important processes by which  renal tubules modulate the volume & composition of urine  precise control of volume, osmolality & pH of the ECF & ICF mediated by transport proteins in cell membranes of the nephron genetic & acquired defects in transport proteins  kidney diseases + many transport proteins  important drug targets Renal handling of glucose Recall that glucose is freely filtered across glomerular capillaries and reabsorbed by the epithelial cells in the 1st half of (or the early) PT The reabsorption of glucose in the early PT involves : – active transport of Na+ at basolateral membrane via Na+/K+ATPase – Na+ moves from the tubular fluid and enters PT cell at apical membrane with glucose (Na+ - glucose symport or Na+ - glucose cotransport) on the Na+ - glucose cotransporter (SGLUT) – glucose leaves the cell and moves into the peritubular capillary blood at basolateral membrane via passive mechanisms (facilitated diffusion) on the glucose transporters GLUT 1 & GLUT 2 Because of limited number of glucose transporters, the mechanism is saturable i.e. it has a transport maximum Tm Glucose Reabsorption in the early PT Figure 6-14; Costanzo, 2022 Glucose Reabsorption in the early PT Figure 6-15; Costanzo, 2022 Glucose Reabsorption in the early PT Renal Tubular Transport Maximum ( Tm) maximum tubular concentration of substance which can be transported per unit time from tubule  blood, e.g. glucose ~ 375 mg/min Renal Threshold plasma concentration of substance at which it begins to appear in the urine, e.g. glucose ~ 180 – 200 mg/dL Glucose Reabsorption in the early PT Filtration : – glucose is freely filtered across glomerular capillaries; filtered load is calculated as GFR x plasma concentration of glucose [P glucose] – as plasma concentration of glucose increases, filtered load increases linearly Glucose Reabsorption in the early PT Reabsorption : – Tm for glucose reabsorption = 375 mg/min = maximum concentration of glucose that can be transported per unit time from the tubular fluid back into the blood – the amount of glucose transported is proportional to the amount present in tubular fluid (amount filtered) up to the Tm for glucose – a higher concentrations, the Tm is saturated and there is no increase in the amount transported Glucose Reabsorption in the early PT Normal plasma glucose level = 80 -100 mg/dL – when plasma conc = 100 mg/dL, assuming GFR = 125 ml/min then : filtered load = GFR x plasma concentration of glucose = 1.25 dL/min x 100 mg/dL = 125 mg/min – 125 mg/min, which is < Tm, so all glucose is reabsorbed & none excreted in urine Glucose Reabsorption in the early PT Excretion – Below plasma glucose concentrations of 200 mg/dL, all of the filtered glucose is reabsorbed and none is excreted – At plasma glucose concentrations > 200 mg/dL, some of the filtered glucose is not reabsorbed because the carriers are getting saturated – The plasma concentration at which glucose is first excreted in the urine is called threshold – just over 200 mg/dL in this graph – Above 350 mg/dL, Tm is reached and the carriers are fully saturated – The curve for excretion now increases linearly as plasma glucose concentration increases and parallels that for filtration Glucose Reabsorption in the early PT The Tm for glucose is approached gradually, rather than sharply- this is called splay Splay is that portion of the titration curve where reabsorption is approaching saturation, but it is not fully saturated Because of splay, glucose is excreted in the urine at threshold, before the reabsorption levels off at Tm Renal handling of glucose Why does splay occur ? – Low affinity of Na+ glucose transporter for glucose as the glucose concentration in the tubular fluid rises, if glucose molecules detach from their transporter protein SGLT, those glucose molecules will be excreted because of the few remaining “free” transporters to which they may re-attach – Heterogeneity of nephrons Tm represents the Tm for the whole kidney all the nephrons in the kidney do not have the same Tm; some will reach Tm at lower plasma concentrations than others and glucose will be excreted in the urine in those nephrons before others Renal handling of glucose at normal plasma glucose concentrations, 80 – 100 mg/dL, all of filtered glucose is reabsorbed and none is excreted (see graph) – no glucosuria Glucosuria uncontrolled DM – the plasma glucose concentration > Tm  glucosuria pregnancy – GFR is ,   filtered load of glucose so that it may > reabsorption of glucose Na+- glucose cotransporter – congenital abnormalities of the transporter   Tm Mini - Quiz 1. The concentration of glucose in plasma is 100 mg / dL and the GFR is 125 mL / min. How much glucose is filtered per minute? Mini - Quiz 1. The concentration of glucose in plasma is 100 mg / dL and the GFR is 125 mL / min. How much glucose is filtered per minute? This is the filtered load of glucose. The amount of a substance filtered per unit time is given by the product of GFR and the filterable plasma concentration of the substance. In this case, 125 mL /min X 100 mg / 100 mL = 125 mg / min. (1 dL = 100 mL) Mini - Quiz 2. In a diabetic patient, the concentration of glucose in plasma is 300 mg / dL and the GFR is 140 mL / min. Estimate the glucose excretion rate. Use the Tm information from the graph. Glucose Reabsorption in the early PT Figure 6-15; Costanzo, 2022 Mini - Quiz 2. In a diabetic patient, the concentration of glucose in plasma is 300 mg / dL and the GFR is 140 mL / min. Estimate the glucose excretion rate. Use the Tm information from the graph. The filtered load of glucose = 140 mL /min X 300 mg / 100 mL = 420 mg / min. (1 dL = 100 mL) Excretion Rate = Filtered Load – Reabsorption Rate Reabsorption Rate ~ 375 mg/min Excretion Rate = 420 – 375 mg/min = 45 mg/min Today’s Topics Measurement of Reabsorption & Secretion Solute and water transport along the nephron – Renal handling of glucose – Early Proximal Tubule Reabsorption of Na+ coupled with glucose, amino acid, bicarbonate, phosphate, lactate & citrate – Late Proximal Tubule Reabsorption of NaCl – – – – – Isosmotic reabsorption in the PT Glomerulotubular Balance in the PT Loop of Henle Early Distal Tubule Late Distal Tubule & Collecting Duct Sodium Balance Na+ - major cation of the ECF amount (content) determines ECF volume (plasma volume blood volume and blood pressure) renal mechanisms involved in reabsorption of Na+ are critically important for the maintenance of a normal ECF volume, normal blood volume and normal blood pressure reabsorption processes for many other substances (e.g. glucose, amino acids, chloride, water are dependent on Na+ reabsorption Sodium Balance Positive Na+ balance – Na+ intake > Na+ excretion – Extra Na+ is retained in the body – ECF   ECF volume or ECF expansion Negative Na+ balance – Na+ excretion > Na+ intake –  Na+ content in the body – ECF   ECF volume or ECF contraction Na+ handling in the nephron Figure 6-19; Costanzo, 2022 Overview of Na+ handling in the nephron Na+ freely filtered across glomerular capillaries ~ 67% of filtered load of Na+ reabsorbed in the PT (water follows Na+ : isosmotic) ~ 25% of filtered load of Na+ reabsorbed in the thick ascending limb of LoH (thick ascending limb of LoH NOT permeable to water) ~ 8% of filtered load of Na+ reabsorbed in the DT & CD – ~ 5% of filtered load of Na+ reabsorbed in the early DT (early DT NOT permeable to water) – ~ 3% of filtered load of Na+ reabsorbed in the late DT & CD (late DT & CD permeable to water in presence of ADH) – late DT & CD responsible for fine tuning of Na+ reabsorption site of action of aldosterone Proximal Tubule reabsorbs : – approximately 67% of filtered Na+, water, Cl-, K+, and other solutes – virtually all the glucose & amino acids filtered by the glomerulus reabsorption of every substance, including water, is linked to the operation of Na+,K+-ATPase in the basolateral membrane of PT Na+ handling in the nephron Figure 6-19; Costanzo, 2022 Na+ Reabsorption in the early PT Figure 6-20; Costanzo, 2022 Na+ Reabsorption in the early PT HCO3 H2CO3 CO2 + + H2O CO2 H2O H2CO3 H+ H+ HCO3 - Figure 6-20;6-20; modified; Costanzo, Figure Costanzo, 2014.2022 Na+ Reabsorption in the early PT Early PT Na+ entry to PT cell coupled to entry of organic solutes – Na+ enters proximal cells via several symporter or cotransport mechanisms on the luminal membrane including Na+-glucose, Na+-amino acid, Na+-Pi, and Na+-lactate , Na+-citrate – glucose and other organic solutes that enter the cell with Na+ leave the cell across the basolateral membrane via passive transport mechanisms Na+ Reabsorption in the early PT Early PT Modifications to original filtrate – 100% filtered glucose & amino acids reabsorbed – 85% filtered HCO3- reabsorbed – Most of filtered phosphate, lactate, citrate – Most of filtered Na+ reabsorbed Lumen negative potential difference across cells of the early PT – Created by Na+ -glucose and Na+-amino-acid cotransporters – Bring net positive charge into the cell and leave negative charge in the lumen Na+ Reabsorption in the late PT Late PT Tubular fluid has high [Cl-] – Recall HCO3- has been absorbed in the early PT leaving behind Cl-in the tubular fluid – Also, water has been reabsorbed isoosmotically along with solute  [Cl-] to increase Late PT absorbs mainly NaCl – High tubular [Cl-] is driving force for this reabsorption – Transcellular pathway: 2 exchange mechanisms : Na-H+ exchange and Cl- - formate anion exchanger – Net result : reabsorption of NaCl Na+ Reabsorption in the late PT Late PT Late PT absorbs mainly NaCl – High tubular [Cl-] is driving force for this reabsorption – Paracellular pathway: Diffusion of Cl- down its concentration gradient through leaky “tight” junctions between cells of the PT and into the blood This movement of negatively charged Cl- creates a positive potential difference in the lumen and this drives Na+ to follow Cl- – Net result : reabsorption of NaCl Na+ Reabsorption in the late PT H+ HCOOH HCOO- FigureFigure 6-21 modified; Costanzo, 2022 6-21; Costanzo, 2014. Isosmotic Reabsorption in the PT Isoosmotic reabsorption characteristic of PT Solute & water reabsorption are coupled and proportional to each other – The solutes : major cation : Na+; major anions HCO3- & Cl– Minor anions : phosphate, lactate, citrate – Other solutes : glucose , amino acids Isosmotic Reabsorption in the PT Figure 6-22; Costanzo, 2022 Isosmotic Reabsorption in the PT Routes of solute & water reabsorption – Na+ enters cell across luminal membrane & water follows to maintain isosmolarity (Step 1 in diagram) – Na+ is pumped out of the cell by Na+-K+ ATPase located on the basolateral membrane & water follows passively (Step 2a&b) – The isoosmotic fluid that accumulates in the lateral intercellular spaces between the PT cells is then acted upon by Starling’s forces in the peritubular capillary (Step 3) The high oncotic pressure of peritubular capillary blood (created by glomerular filtration) favors reabsorption of isosmotic fluid Glomerulotubular Balance in the PT Major regulatory mechanism of the PT for controlling tubular reabsorption – describes the balance between filtration and reabsorption – ensures that a constant fraction (67% of filtered load) of the filtered load is reabsorbed by the PT, even if filtered load increases or decreases Glomerulotubular Balance in the PT Major regulatory mechanism of the PT for controlling tubular reabsorption – mechanism – filtration fraction & Starlings forces in peritubular capillary blood – E.g.  in GFR, at constant RPF in the afferent arteriole   FF (recall FF = GFR / RPF)  higher than usual fraction of fluid is filtered out of the glomerular caplillary  leaving behind  [plasma proteins] in the efferent arteriole & peritubular capillary   π pc –  π pc   reabsorption of isosmotic fluid – therefore the proportionality of filtration and reabsorption is maintained Glomerulotubular Balance in the PT G-T Balance can be altered by changes in ECF volume ECF volume expansion – produces a decrease in fractional reabsorption in the PT – E.g.  in ECF volume e.g. infusion of isotonic NaCl   (oncotic pressure in the peritubular capillaries) π pc and  (capillary hydrostatic pressure) Pc – both of these forces produce a decrease in fractional reabsorption of isosmotic fluid at the PT – the fluid that is not reabsorbed is excreted – this aids in the excretion of excess NaCl and water when there is ECF volume expansion Effect of changes in ECF volume on isosmotic fluid reabsorption in the PT Figure 6-24; Costanzo, 2022 Glomerulotubular Balance in the PT G-T Balance can be altered by changes in ECF volume ECF volume contraction – produces an increase in fractional reabsorption in the PT – E.g.  in ECF volume e.g. diarrhea or vomiting   (oncotic pressure in the peritubular capillaries) π pc and  (capillary hydrostatic pressure) Pc – both of these forces produce an increase in fractional reabsorption of isosmotic fluid at the PT Glomerulotubular Balance in the PT G-T Balance can be altered by changes in ECF volume ECF volume contraction – also activates renin-Ag-Aldosterone system – Ag II stimulates Na-H+ exchange in the PT   reabsorption of Na+ and water since this mechanism specifically stimulates HCO-3 reabsorption  “contraction alkalosis” Today’s Topics Measurement of Reabsorption & Secretion Solute and water transport along the nephron – Renal handling of glucose – Early Proximal Tubule Reabsorption of Na+ coupled with glucose, amino acid, bicarbonate, phosphate, lactate & citrate – Late Proximal Tubule Reabsorption of NaCl – – – – – Isosmotic reabsorption in the PT Glomerulotubular Balance in the PT Loop of Henle Early Distal Tubule Late Distal Tubule & Collecting Duct Na+ handling in the nephron Figure 6-19; Costanzo, 2022 Loop of Henle Thin descending limb – Highly permeable to water and moderately permeable to small solutes e.g. NaCl & urea Thin ascending limb – Permeable to NaCl – Impermeable to water Thick ascending limb – Permeable to NaCl – Impermeable to water – Actively reabsorbs ~ 25% of filtered Na+ – Reabsorption of Na+ is “load dependent” Na+ reabsorption in the Thick Ascending Limb Figure 6-25; Costanzo, 2022 Na+ reabsorption in the Thick Ascending Limb Luminal membrane – Na+- K+- 2Cl- cotransporter – K+ channels Basolateral membrane – Na+-K+ ATPase – K+ & Cl- channels Na+, K+ & Cl- are reabsorbed into cell; Na+ is moved out of cell by Na+-K+ATPase and K+ and Cl- diffuse through channels down their electrochemical gradients Some K+ diffuses back into the lumen, making the lumen slightly positively charged (this helps with driving the reabsorption of cations e.g. Ca2+, Mg2+) Na+ reabsorption in the Thick Ascending Limb cells of the thick ascending limb are impermeable to water, so water is not reabsorbed along with the NaCl; water remains behind in the tubular fluid, diluting it. For this reason the thick ascending limb is called the “diluting segment”. The tubular fluid leaving the thick ascending limb and entering the early distal tubule has a lower osmolarity than blood or is hypotonic (~ 100 mOsm/L) thick ascending limb is the site of action of “loop diuretics” e.g. furosemide. At physiologic pH, loop diuretics are anions that attach to the Cl- binding site of the Na+- K+-2Clcotransporter causing the transporter to stop cycling   NaCl reabsorption   excretion of NaCl Today’s Topics Measurement of Reabsorption & Secretion Solute and water transport along the nephron – Renal handling of glucose – Early Proximal Tubule Reabsorption of Na+ coupled with glucose, amino acid, bicarbonate, phosphate, lactate & citrate – Late Proximal Tubule Reabsorption of NaCl – – – – – Isosmotic reabsorption in the PT Glomerulotubular Balance in the PT Loop of Henle Early Distal Tubule Late Distal Tubule & Collecting Duct Na+ handling in the nephron Figure 6-19; Costanzo, 2022 Early Distal Tubule Early DT: reabsorbs ~ 5% of filtered Na+ – Reabsorption of Na+ is “load dependent” Luminal membrane – Na+-Cl- cotransporter Basolateral membrane – Na+-K+ ATPase – Cl- channels Na+ & Cl- are reabsorbed into cell; Na+ is moved out of cell by Na+K+-ATPase and Cl- diffuses through its channel down its electrochemical gradient Early DT is impermeable to water (like thick ascending limb), so NaCl is reabsorbed but water is left behind in tubules which further dilutes the (already diluted) tubular fluid. For this reason the early DT is called the “cortical diluting segment” Na+ Reabsorption in the Early Distal Tubule Figure 6-26; Costanzo, 2022 Early Distal Tubule Na+- Cl- cotransporter of the early DT is different from the Na+K+-2Cl- cotransporter in 3 ways : – it transports 2 ions – it is electro-neutral (does not create a charge difference in the tubular lumen with respect to the cells of the early DT) – it is inhibited by a different class of diuretic : thiazide diuretics e.g. chlorothiazide at physiologic pH, these diuretics are anions and bind to Cl- site of Na+- Cl- cotransporter causing the transporter to stop cycling   NaCl reabsorption Today’s Topics Measurement of Reabsorption & Secretion Solute and water transport along the nephron – Renal handling of glucose – Early Proximal Tubule Reabsorption of Na+ coupled with glucose, amino acid, bicarbonate, phosphate, lactate & citrate – Late Proximal Tubule Reabsorption of NaCl – – – – – Isosmotic reabsorption in the PT Glomerulotubular Balance in the PT Loop of Henle Early Distal Tubule Late Distal Tubule & Collecting Duct Na+ handling in the nephron Figure 6-19; Costanzo, 2022 Late Distal Tubule and Collecting Duct late DT & CD : reabsorb ~ 3% of filtered Na+ – Reabsorption of Na+ is “load dependent” although small compared to other segments, they make fine adjustments to Na+ reabsorption Principal cells – Na+ reabsorption, K+ secretion, water reabsorption - intercalated cells – K+ reabsorption – H+ secretion Na+ Reabsorption in the Late DT & CD Figure 6-27; modified; Costanzo, 2022 Late Distal Tubule and Collecting Duct Luminal membrane – Na+ channels – K+ channels Basolateral membrane – Na+-K+ ATPase Na+ diffuses through Na+ channels on the luminal membrane; Na+ is moved out of cell by Na+-K+-ATPase; Cl- accompanies Na+, but transport mechanism for Cl- is unknown K+ diffuses out of cell into lumen Late Distal Tubule and Collecting Duct Na+ reabsorption in the principal cells – stimulated by aldosterone – inhibited by K+ -sparing diuretics e.g. amiloride, spironolactone spironolactone blocks the action of aldosterone  inhibits Na+ reabsorption (& K+ secretion) amiloride binds to luminal Na+ channels and inhibits Na+ reabsorption – “K+ -sparing” diuretics are drugs that reduce K+ secretion from the principal cells into the tubular lumen (via the luminal K+ channel) and therefore reduce K+ excretion – often used together with loop or thiazide diuretics to offset  K+ secretion &  K+ excretion & resultant hypokalemia produced by these drugs Late Distal Tubule and Collecting Duct water reabsorption in the principal cells – variable depending on the presence of ADH – low /absent ADH  low water permeability of principal cells – high ADH  high water permeability of principal cells