Tubular Transport Lecture 26 Fall 2024 PDF

1502 Tubular Transport Fall 2024 Lecture 26 Tuesday, Oct 22: 10am Dr. Layla Al-Nakkash...

1502 Tubular Transport Fall 2024 Lecture 26 Tuesday, Oct 22: 10am Dr. Layla Al-Nakkash [email protected] 1 © L. Al-Nakkash 2020  Learning Objectives 1. Describe the components of renal function: reabsorption and secretion. 2. Examine sodium balance in the proximal tubule. 3. Examine sodium balance in the thick ascending limb 4. Examine sodium balance in the distal tubule and collecting duct. 5. Describe the tubular maxima. 6. Describe the relationship between plasma glucose and glucose reabsorption: glucose titration curve. 7. Describe glucosuria. 2  Components of Renal Function Glomerular Filtration (GF) – Filtration of a protein-free plasma from the glomerulus into the Bowman’s capsule Tubular Reabsorption (TR) – Selective movement of filtered substances from the tubular lumen into the peritubular capillaries Tubular secretion (TS) – Selective movement of nonfiltered substances from the peritubular capillaries into the tubular lumen Urine excretion – Elimination of water and substances from the body © L. Al-Nakkash 2024 1. Describe the components of renal function: reabsorption and secretion. 3  Sodium balance in the proximal tubule Sodium reabsorption by the kidneys is an important function. Sodium control is key to maintaining ECF volume, normal blood volume and blood pressure. Recall: Sodium balance needs to be maintained. – If Na+ excretion is < intake, one is in ___________________ Positive sodium balance retaining Na+ – If Na+ excretion is > intake, one is in ___________________ Negative sodium balance losing Na+ © L. Al-Nakkash 2024 2. Examine sodium balance in the proximal tubule. 4  Sodium balance in the proximal tubule The majority of Na+ reabsorption is in the * proximal convoluted tubule. Here 2/3 of Na+ reabsorption 2/3 of Na+ occurs. In the PCT, water reabsorption With water * reabsorption is linked to Na+ Isosmotic reabsorption. mechanism 1/4 of Na+ The thick ascending limb reabsorption reabsorbs ¼ of the filtered Without water load of Na+. impermeable to water The last step of Na+ reabsorption in the DCT and CD (*) is regulated by aldosterone © L. Al-Nakkash 2024 2. Examine sodium balance in the proximal tubule. 5  Sodium balance: early proximal tubule 6 © L. Al-Nakkash 2024 2. Examine sodium balance in the proximal tubule. 6  Sodium balance: early proximal tubule Most essential solutes are reabsorbed here. Many secondary active transporters- deriving energy from the ________. Na+ gradient Cotransport mechanisms: – __________________ Na+ -glucose (SGLT), Na+ -amino acid, __________________ Na+ -lactate, citrate or phosphate __________________ Sodium moves into the cell down its electrochemical gradient coupled to The Na+/H+ exchanger these solutes. (apical membrane) and bicarbonate diffusion Sodium is removed from the cell via (basolateral membrane) are key for acid/base the _____________ Na+ /K+ - ATPase The solutes exit via facilitated diffusion balance 7 © L. Al-Nakkash 2024 2. Examine sodium balance in the proximal tubule. 7  Sodium balance: late proximal tubule At this point in the nephron- tubular fluid should be different from the original filtrate from the glomerulus. Why? we have reabsorbed from the tubular fluid: glucose, amino acids, etc. The fluid here should be devoid of all these solutes. Fluid here has a high [Cl-]. This region primarily reabsorbs NaCl. What would drive this? the high - tubular [Cl ] The Na /H exchanger and the Cl- + + Na+ & Cl- will also move via the /formate exchanger drive NaCl paracellular pathway absorption into the cell. NaCl exits via__________________. Na+/K+ATPase & Cl- diffusion 8 © L. Al-Nakkash 2024 2. Examine sodium balance in the proximal tubule. 8  Sodium balance: thick ascending limb Reabsorption of ~25% of Na+ occurs here. It is load-dependent, what would this mean? more Na+ delivered → more reabsorbed The apical membrane has the Na/K/2Cl cotransporter. The energy driving this cotransporter comes from the Na+ gradient maintained by the _____________. Na+ /K+-ATPase Most of the K+ that comes in on the Na/K/2Cl cotransporter exits across This is the site of action of loop diuretics: the basolateral membrane and some furosemide, bumetanide. recycles across the apical ↓ NaCl absorption membrane back into the tubular fluid. They will _____ 9 © L. Al-Nakkash 2024 3. Examine sodium balance in the thick ascending limb 9  Sodium balance: early distal tubule Reabsorption of ~5% of Na+ occurs here. The apical membrane has the NaCl cotransporter. The energy driving this cotransporter comes from the Na+ gradient maintained by the _____________. Na+ /K+-ATPase Here there is net NaCl reabsorption: – Na+ exits across the basolateral membrane on the Na+/K+ -ATPase and Cl- exits the basolateral membrane diffusing through chloride channels. This is the site of action of thiazide diuretics: chlorothaizde, hydrochlorothiazide, metalozone. ↓ NaCl absorption They will ____ 10 © L. Al-Nakkash 2024 4. Examine sodium balance in the distal tubule and collecting duct 10  Sodium balance: late distal tubule & collecting duct Reabsorption of ~3% of Na+ occurs here. The apical membrane has sodium channels:_____. ENaC’s Sodium enters the channels down its electrochemical gradient. Na+ exits across the basolateral membrane via the ___________. Na+ /K+-ATPase This is the site of action of K+ sparring diuretics: amiloride, spironolactone. ↓ They will ______ Na absorption Why would they produce mild diuresis? They would inhibit only a small % 11 of the total Na reabsorption. © L. Al-Nakkash 2024 4. Examine sodium balance in the distal tubule and collecting duct 11  Sodium balance: late distal tubule & collecting duct Reabsorption of Na+ here is also regulated by aldosterone.  Na+ Aldosterone will ____ reabsorption.  Aldosterone will ____ ENaC channel production and insertion it can also increase Na+ /K+-ATPase protein expression 12 © L. Al-Nakkash 2024 4. Examine sodium balance in the distal tubule and collecting duct 12  Tubular Maxima The tubular maximum (Tm) is the maximal rate that a solute is being transported. Measured in mg/min It occurs due to saturation of transporters. Below the Tm: all the filtered load is reabsorbed. Above the Tm: the solute is excreted. Tm’s are found in the proximal tubule 13 © L. Al-Nakkash 2024 5. Describe the tubular maxima  Glucose Reabsorption Filtered across the glomerulus and then reabsorbed in the proximal tubule A 2-step process that saturates. A limited number of transporters Tubular Peritubular fluid capillary blood Sodium enters via Na+-glucose cotransporters. The energy driving this comes from? Na+/K+-ATPase Na+-glucose cotransport is a secondary active transport ATP directly provides energy for the pump & Na+-glucose indirectly maintains the Na gradient bringing cotransport in glucose SGLT facilitated Sodium leaves via facilitated transport diffusion. No energy needed GLUT1 and GLUT2 carriers 14 14 © L. Al-Nakkash 2024 6. Evaluate how glucose is reabsorbed.  Glucose Titration Curve and Tm The relationship between plasma [glucose] and glucose reabsorption. Glucose titration curve: obtained by infusion with glucose and measuring rate of reabsorption as the plasma [glucose] increases. Tm: maximum rate at which glucose can be reabsorbed. When plasma [glucose] is less than 200 mg/dL, all the filtered glucose is The filtered and reabsorbed reabsorbed. lines overlap When plasma [glucose] is greater than 200 mg/dL, only some of the filtered glucose is reabsorbed. dL = 100ml At 350 mg/dL, reabsorption levels off, at the maximal value = Tm At Threshold – the [plasma] when we see the All carriers are saturated substance –glucose- in the urine 15 7. Assess the relationship between plasma glucose and glucose reabsorption: glucose titration curve. 15 © L. Al-Nakkash 2024  Glucose Titration Curve and Tm The relationship between plasma [glucose] and glucose reabsorption. Filtered load: glucose is filtered across the capillaries FL= GFR x Plasma [glucose] As Plasma [glucose] ↑ then Filtered load increases linearly. Excretion: below 200 mg/dL all filtered glucose is reabsorbed. There are ample Na/glucose carriers. Above this concentration the glucose carriers saturate. Glucose that is not reabsorbed is excreted. The [plasma] when this occurs is known as? threshold Once the carriers are saturated at Tm, then glucose is excreted. As Plasma [glucose] ↑ then excretion rate increases linearly. 16 16 © L. Al-Nakkash 2024 7. Assess the relationship between plasma glucose and glucose reabsorption: glucose titration curve.  Glucose Titration Curve and Tm The relationship between plasma [glucose] and glucose reabsorption. Splay: Splay is the portion of the titration curve where reabsorption approaches full saturation. But, is not quite there yet Glucose is excreted in the urine before reabsorption levels off at Tm. Why does splay occur? – Heterogeneity of nephrons. – Tm reflects the average for all the kidney – Nephrons will behave differently Reflects saturation kinetics of millions of nephrons 17 17 © L. Al-Nakkash 2024 7. Assess the relationship between plasma glucose and glucose reabsorption: glucose titration curve.  Glucosuria – At normal plasma [glucose] all the filtered glucose is reabsorbed, none excreted. 70-100 mg/dL – Uncontrolled diabetes mellitus: ↑ plasma [glucose] results in filtered load for glucose > reabsorptive capacity. Plasma [glucose] > Tm, glucose is excreted – Genetic abnormalities in the SGLT: associated with decreased Tm, and glucose will be excreted. 18 © L. Al-Nakkash 2024 8. Describe glucosuria  The majority of Na is reabsorbed in the collecting duct True / False If Na excretion is < intake – we have positive Na balance True / False Most essential solutes are reabsorbed from the proximal convoluted tubule True / False In the late proximal tubule NaCl can pass through the paracellular pathway True / False Aldosterone will decrease Na reabsorption True / False Tm is the minimum rate at which glucose can be reabsorbed True / False Splay is the portion of the titration curve where reabsorption approaches saturation True / false © L. Al-Nakkash 2024 19  The majority of Na is reabsorbed in the collecting duct True / False Proximal convoluted tubule 67% If Na excretion is < intake – we have positive Na balance True / False We are retaining more Na Most essential solutes are reabsorbed from the proximal convoluted tubule True / False Reabsorbed from the PCT: Na-coupled transport Glucose, amino acids In the late proximal tubule NaCl can pass through the paracellular pathway True / False Aldosterone will decrease Na reabsorption True / False Increasing it With more ENaC insertion Tm is the minimum rate at which glucose can be reabsorbed True / False The Maximal rate of solute transport Splay is the portion of the titration curve where reabsorption approaches saturation But it’s not quite there yet. True / false Splay occurs due to nephron heterogeneity © L. Al-Nakkash 2024 20