Lecture 24

Re-absorption by the Kidney: (Absorption of the nephron)

• Remember the cells with the Tight Junctions in between them.  Tight Junction allow things to pass through them, and they seem to be selective
  
• The Interstitium is on the right
  
• The Lumen of the nephron is on the left
  
• The Apical membrane is on the left side going from Tight Junction to Tight Junction, and the Basolateral membranes is on the right side going from Tight Junction to Tight Junction.
  
• We have a Basilar Membrane that these cells are sitting upon, but the Basilar Membrane is so porus that things get by it very easily
  
• As reabsorption takes place there are two transports that can occur.
  
  • We can transport thing out of this Lumen across the cell, and have it come into the cell on the Apical Membrane side, and then have it get kicked out of the cell on the Basolateral Membrane side – that is called the Transcellular Route
    
  • When we have things that are moving in through Tight Junctions – that is called the Paracellular Pathway
    
• In anatomy we talked about the Convoluted and Straight Proximal Tubule, but in Physiology we talk about the Early and the Late Proximal Tubule
  
• Reabsorption starts in the Early Proximal Tubule
  
• Main propulsion for reabsorption is achieved by Sodium Potassium Pumps. They are ATP powered.
  
  • There are not many things in the kidney that are ATP powered.
    
  • They are normal pumps that we find in any cell, but there are many of them.  Sodium is in the same proportion as everything else here so we have to have a reason to kick it back in here, so we have Sodium Potassium Pumps, and we have Sodium being kicked out and we have Potassium being kicked in (the same as any other cell)
    
  • The kidney cells are not the same b/c the Basolateral Membrane has a ton of Sodium Potassium Antiports/Pumps (There are no sodium potassium pumps in the apical membranes, it has potassium leak channels in both direction, but they only exist on one side of the cell).  There is a low concentration of Sodium within the cell, but there is a high concentration of Sodium in the lumen.  This gradient causes the Sodium to go into the cell.
    
  • There are a lot of Co-transports for the Sodium on the Apical Membrane driven by this gradient.  A lot of what is being transported in is Sodium, and Sodium is being transported in with:
    
    • Glucose
      
    • Amino Acids
      
    • Inorganic Phosphate
      
    • Sulfate
      
    • Organic Acid
      
  • There is one Antiport of note in the Early Proximal Tubule, and that is the Antiport where there is a Hydrogen Ion in the cell and that is going out in response to Sodium going in.  The gradient for Sodium is what is kicking the Hydrogen ion out into the lumen making the urine more acidic.
    
    • Normally Chlorine follows Sodium around like a little dog, and Cl is higher on the outside of the membrane b/c the Sodium went out and the Cl followed it. However, in the Early Proximal Tubule there is a bunch of Na coming in, but instead we are sending out Bicarbonate (HCO3-), which is a negative ion.
      
    • Charged ions (HCO3-) have trouble coming across here.  The Bicarbonate cannot cross the membrane or the Paracellular Route in its charged ion form.
      
    • Cl doesn't follow the Na b/c Cl is shut out here, rather the HCO3- is in the Interstitium on the right side and changes its form so that it can get into the Interstitium. (Explained how it gets in there in another lecture.  It changes forms.)
      
    • Tons of Na and HCO3- are coming in.  The moving of the ions here will increase the osmotic gradient in the Interstitium and water is being drawn out of the lumen and into the Interstitium with the ions.  Whenever we set up sodium and bicarbonate or chlorine to pull the water out of the lumen it is called Obligatory Water Reabsorption.
      
    • Sodium pulls out the bicarbonate and lots of water, but what is happening is the lumen is loosing water, and what solids remain in the lumen is becoming more concentrated. Things that did not have concentration gradients to get out of the tube now have concentration gradients to pull them across the tube, and they sometimes go with the water – this is called Solvent Drag.
      
      • Na pumps are the major reason why we have a lot of reabsorption
        
    • The Tight Junctions in the proximal tubule are leaky to water and most of the water is going in via the Paracellular Route, but they are also very selective.  Some water is going in via the Transcellular route.
      
    • In the early proximal tubule, if you have any proteins that happen to get through, the cell is doing this by Pinocytosis through the Apical Membrane. After this occurs the cell digests them down to their amino acid constituents, which are passed into the Interstitum.  Proteins never reach the Interstitium, only their amino acids do.
      
• The Late Proximal Tubule – we differentiate because the Tight Junctions are not the same. In the Late Proximal Tubule Cl can go through. By time we get to the Late Proximal Tubule, most of these things have been absorbed and all these co-transports for the Na are doing very well.
  
  • There is a Sodium-Hydrogen ion Antiport. Sodium is moving in and Hydrogen ion going out with this pump. 
    
  • By the time the filtrate reaches the Late Proximal Tubule all of the solutes (Glucose, Amino Acids, Inorganic Phosphate (stopped reabsorbing), Sulfate, and Organic acids) are gone.
    
  • Most of the Na is getting pumps the Hydrogen ions out via the Sodium-Hydrogen Ion Antiport.  The minority of the things were being transported by this in the early proximal tubule.
    
  • The Chlorine has been concentrating out in the lumen, and it is very highly concentrated in the Late Proximal Tubule (b/c HCO3- was following Na+ around).  Now Cl starts to come in by the Paracellular Route really quickly.  Since so much Cl- comes in negatively charged, it pulls a little positively charged Na+ in also.
    
  • There is also a Chlorine Anion Antiport, where Cl- goes in and the Anion goes out in the Apical Membrane in the Late Proximal Tubule. There is an exchange of a negative charges.
    
  • Cl- also pours through the Paracellular membrane
    
    • If you have a charge you cannot cross the plasma membrane. If you are neutral in charge it is really easy to go through the plasma membrane.
      
    • The hydrogen ion (+) and anion (-) that came out bind, and they become neutral – the neutral complex just goes back into the cell – this recycles/cycles the Cl- and brings it back into the cell.
      
    • There is a Co-transport of K+ and Cl- into the interstitum, and the K+ gets picked back up by the ATP pumps.
      
• Thin Descending Loop of Henle
  
• Neither of the Thin Descending or Thin Ascending Loop of Henle actively pump Na+ out into the intersititum.
  
• There are very few Sodium Potassium Pumps in these cells, and there is also no ATPase to run them.
  
  • Water passes easily out of the Thin Descending Loop of Henle.
    
  • Small amounts of Na and Cl can transport across the membrane.  Sodium passes into the tubule not out of the Tubule.
    
• The Medulla – contains the Thin Descending to Thin Ascending Loop of Henle, along with the Thick Ascending Loop of Henle. The Thick Ascending Loop of Henle is in the outer-medullar area and the Thin Descending/Ascending Loop of Henle are in the Inner medullary area.
  
  • Medulla of the Kidney:
    
    • Outer Portion:
      
      • The Outer portion of the Thin Descending Loop of Henle is NOT permeable to urea.
        
    • Inner Portion:
      
      • The Inner portion of the Thin Descending Loop of Henle is fairly permeable to Urea. The urea is flowing in to the Tubule, not out.
        
• Thin Ascending Loop of Henle
  
  • The Thin Ascending Loop of Henle is not permeable to water.
    
  • Sodium and Chlorine can easily move out of here.
    
  • The Thin Ascending Loop of Henle is fairly permeable to Urea, but at this point it is moving in
    
• Thick Ascending Loop of Henle
  
  • The Thick Ascending Loop of Henle is impermeable to Urea and Water.
    
    • There are Sodium Hydrogen Ion Antiports present here. 
      
    • There is a special co-transport that causes the greatest movment of Sodium into the cell while also taking in Sodium/Potassium/2 Chlorine.  There are also a ton of Sodium Potassium pumps on the Basolateral side pumping out Sodium.
      
    • There are Potassium Leak Channels in both the Interstitium and Lumen, which increase the uptake of Potassium at this point.
      
    • In the Basolateral Membrane we have a lot of Sodium Potassium Pumps, so we are talking about Na and Cl going out at this point
      
    • It kicks out a whole lot of sodium and chlorine.
      
    • This has more sodium and chlorine pumps than we had in the proximal tubule.
      
    • We have water coming down here, and very little Na and Cl.  As we went through the first parts of the nephron (the Early and Late Proximal Tubule) and we lost Na, and we were losing as much water as we were ions.  So we stayed at the same osmotic gradient all the way to the end of the Straight Tubule.  Then the Na and Cl can't come out anymore, and water starts to pour out of this thing. The Na and Cl are going to get very concentrated in the Descending Loop, until it gets around the corner to the Ascending Loop and water cannot get out, but the Na and Cl pour out.  So what happens to the water?
      
    • When you think of this, think of water coming in and the Na and Cl coming out (staying there), but the water gets taken up by the Vasa Recta and it just goes away.
      
    • When we talk about water coming out into the Interstitium disappearing right away by the Vasa Recta, it follows the Loops of Henle of the Juxtamedullary Nephrons.
      

       
       

 
 

 
 

 
 

 
 

Screen clipping taken: 3/23/2009, 12:24 PM

 
 

 
 

 
 

Screen clipping taken: 3/23/2009, 12:24 PM

 
 

 
 

The System:

• The blood is 300 milliosmoles – which is a gradient of osmotic pressure. It is actually the number of particles that is creating it.
  
• When it entered this Thin Descending Loop it was at 300 milliosmoles, and then as the water poured out of it, this gradient increased.
  
• So at the bottom of the medulla it will get to 1200 milliosmoles, which is the Maximum in the Innermedually area (the Urine gets very concentrated here b/c a ton of Na and Cl can leave).
  
• Then Na and Cl start to pour out of this thing, and the water actually stays in here, and that is called the Dilution of the Urine (we are taking solutes out of it and leaving water behind)
  
  • 700 of the 1200 milliosmoles are due to the kicking out of the Na and Cl
    
    • The 700 milliosmoles are fairly constant b/c you will always have 700 milliosmoles coming out (the Na is highly concentrated and pouring in here).  Urea is a variable part b/c of the Innermedullary collecting duct (which can be adjusted by the hormones), but there is little variation of this 700 value. 
      
  • 500 of the 1200 milliosmoles are due to the Urea
    
    • The 500 milliosmoles is very variable.  When you take a walk in the desert and your body says "I need to save as much water as possible," and it will use urea mainly to concentrate the urine up to 1200 milliosmoles b/c that is the most flexible one that it has.
      
  • At 1200 milliosmoles there are 500 milliosmoles of Urea in the Inner meduallry collecting duct.  Some of the Urea can travel back to both of these b/c both of these are fairly permeable to Urea, but that sends it out to the filtrate to concentrate it even more in Urine.
    
  • The Urea can also go to the Vasa Recta, but when it gets to the Outer Medullary Area that is where it runs into Thin Descending Loops of Cortical Nephrons (they only have a Thin Descending Loop), and it is permeable to Urea.  Every Ascending Vasa Recta sits very tightly to the Thin Descending Loop of a Cortical Nephron, and it is transferring Urea into that (Urea doesn't go back into circulation as much as you would think).  All of the Ascending Loops go up and are very tight to the Thin Descending Loop of a Cortical Nephron and it is in the Medullary area.
    
• Early Distal Tubule
  
  • The Early Distal Tubule is impermeable to water and urea.
    
  • We continue to get this dilution, so this gets down to 1200 milliosmoles.  It is 100 milliosmoles when it gets to the Early Distal Tubule, and it continues to be diluted (taking out solvents).  It was 300 milliosmoles when it entered into this loop.
    
  • We have a Na and Cl co-transporter into the cell on the Apical Membrane in the Early Distal Tubule. Cl has an open channel into the Interstitium.  The dilution is continuing through the Early Distal Tubule.
    
  • Na leaves via the ATP pump, and Cl will leave via an open chlorine channel.
    
• Late Distal Tubule
  
• Dilution continues through the Early Distal Tubule to the Late Distal Tubule.
  
• Both Distal tubules are impermeable to water and Urea
  
• The Late Distal Tubule  Connecting Duct  Cortical Collecting Duct  Medullary Collecting Duct (which is made of 3 sections: 1.) a part in the cortex called the Cortical Collecting Duct, 2.) theOuter Medullary Collecting duct b/c it goes down through the medulla and empties urine into the minor calyces, and 3.) the Inner Medullary Collecting duct b/c it goes down through the medulla and empties urine into the minor calyces.
  
• These four segments in the pathway above all have the same structure and function.  They are all impermeable to water and Urea.
  
• There are 2 cells types, but one of them has 2 types of cells (so there are 3 total)
  
  • This is why we know that the thick ascending loop of Henley ends right beyond the JAG because we see a change in cell type.
    
  • There are Principle cells and Intercalated cells.
    
• Principle cells are mainly associated with reabsorbing water and sodium.
  
  • We have open Na channels so Na just goes in, and it only allows Na into there to be reabsorbed (Na is still higher in the lumen than it is in the cell).  Na is going to be pumped out by Sodium Potassium Pumps, and K will leak out in both directions.  So the more Na pumped out the more K leaks out.
    
  • There are two hormones here called are Aldosterone and ADH (Anti-diuretic Hormone) – they work in the principle cells.
    
  • Aldosterone is a mineral corticoid, but it had 95% of the activity of the mineral corticoids.  It gets taken up into the cell and goes into the nucleus, and goes to the gene (stimulating the production of mRNA) that makes the Sodium channels and stimulates the gene to make more Sodium Channels. This stimulates Sodium reabsorption by the kidneys by increasing number of Sodium channels.
    
  • ADH regulates the amount of water in your body for reabsorption.  ADH will be in a vacuole, and it sticks to a receptor on the principle cell and causes an increase in Water channels – increases water reabsorption.
    
    • ADH will bind to the ADH receptor on the outside surface of the cell
      
      • Na can come in here, but no water can come in. 
        
    • Whenever you send something into the nucleus to stimulate a gene it takes time. ADH is only adding already created things to the regulation. When speaking about water regulation you are thinking about ADH. Aldosterone will have an effect but it is very slow over a period of time.
      
    • When ADH is present, this vacuole will be a second messenger and it will increase cyclic AMP (cAMP), and this will become part of the Apical membrane and this will open up and all of these water channels open and lots of water is being absorbed.
      
  • If there is no ADH, no water is reabsorbed by a principle cell. There is always a low level of ADH in the body. In absence of ADH, there is no reabsorption of water by principle cells.
    
• Intercalated cells have to do with the movement of hydrogen ions. There are 2 types of Intercalated cells (Type A and Type B):
  
  • Type A: A have an ATP pump in the apical membrane, and it is pumping Hydrogen Ions out. There is a second ATP powered pump that is a Potassium in and Hydrogen ion antiport – there are fewer of these pumps. This is on the side between the lumen and the inside of the cell. 
    
  • This is generally associated with acidosis
    
  • On the side between the inside of the cell and the basolateral membrane:
    
    • Bicarbonate is kicked out and chlorine is kicked out.
      
    • There are Chlorine leak channels
      
    • We have Potassium and Chlorine kicking  that Cl back out – that is a co-transport.
      
    • The Intercalated cell is kicking out a lot of Hydrogen ions making it very acidic, and taking in a lot of Bicarbonate making it very basic (this is how you fight acidosis in the body – one side is acidic and one side is basic)
      
    • Things to fight acidosis. Bicarbonate into the intersititutium and Hydrogen ions into the urine.
      
    • Most of the body is creating acids.
      
    • When the heart stops, they shock you and put bicarbonate in to fight acidosis.
      
  • Type B: there are a lot fewer Type B cells – they fight Alkalosis
    
    • They are reversed.
      
    • There is a Bicarb out/Cl in antiport in the Apical membrane
      
    • Chlorine leak channel still on basolateral side of membrane.
      
    • There is an ATP Hydrogen ion pump in the interstitium to fight the Alkalosis
      
    • Alkalosis is less of a problem in humans (b/c they make more acids), and this is why there are not that many B-cells.
      
  • Intermedullary Collecting Duct (IMCD) – is divided into 2 sections:
    
    • 1.) The Upper 1/3 is called the ImCDi (i = initial section of the Inner Medullary Collecting Duct). It has principle cells and a few Type A Intercalated cells, but no Type B Intercalated cells.
      
    • 2.) The Lower 2/3 is called the IMCDt (t = terminal section of the Inner Medullary Collecting Duct) [originally it was called the IMCD cell, but this cell doesn't exist anyplace and it is similar to a principle cell but it is not one]. This is called an IMCDt cell – it reabsorbes sodium in response to Aldosterone; it adds Water channels like a principle cell, but it can also add Urea channels to the Apical Membrane, which a principle cell cannot do (this is response to ADH). With the presence of Urea Channels, the Urea is going to increase in the Inner Medullary Portion of the Renal Pyramid, which is where ADH will increase urea to increase the osmotic gradient to draw water to concentrate the urine.  It adds these Urea channels in a similar fashion to how the presence of ADH will add Water channels.  These channels are very selective: Water channels only transport water, and Urea channels only transport Urea.  They are different from Principle cells, in the absence of ADH a principle cell will not transport water at all (it need ADH or no water will cross the membrane), but in an IMCDt cell, in the absence of ADH, there will be a basilar level of water and urea passing through the cell of the lower medulla.
      

   
   

  Potassium Excretion:
  

  • Potassium Excretion increases as we increase Na reabsorption. When Aldosterone is being stimulated to increase the Na uptake, it also increases K excretion. It turn, this ATP powered antiport is being sped up.  When there is an increase in the Na coming in, it increases the Sodium Potassium Pump, which increases the amount of K in the cell.  Since there are K leak channels in the Apical Membrane that go in both directions, this increase the amount of loss of K into the interstitium and urine. (Increase Na we take in: Increase K lost)
    

  Calcium:
  

  • Calcium has open channels in the Apical membranes, it is working with its gradient. It is normally being pumped against its gradient. These channels are in:
    
    • Proximal Tubule
      
    • Thick Ascending Loop of Henle
      
    • Early Distal Tubule
      
  • In the Basolateral membrane in the same 3 areas, there are Calcium ATP pumps, and we have the 3 Na in / 1 Ca out Antiport. These are both Ca movers that we see in other tissues. This pumps the Ca out into the interstitium.
    
  • The Proximal Tubule and the Thick Ascending Loop of Henle allow a great deal of Calcium reabsorption through the Paracellular Route.
    
  • There is also a Facilitated Transport via the Paracellular Route in the Thick Ascending Loop of Henle for Calcium or Magnesium. This facilitated transport is the only known Facilitated Transport that exists in the Tubular Tight Junctions. The Tight Junctions are selective in what they let through not what they seek out.
    

  Phosphate:
  

  • Phosphate can be reabsorbed by the Distal Tubules. 
    

  (See Percent Reabsorption by Nephron Section Handout)
  

  • 80% of the Phosphate is reabsorbed in the Proximal Tubule.
    
  • The Distal Tubule only reabsorbes phosphate in times of deficiency. (If there is no deficiency  0%)
    
  • We have 2 things:
    
  • 1.) Creatinine – is a naturally occurring breakdown product of protein metabolism, and it is freely filtered by the Glomerulus (percentage in the blood = percentage in filtrate), it is only slightly reabsorbed and it has a 10% secretion rate, and it is used to determine GFR – they do a Creatinine Clearance Test to determine the filtration rate – and they measure the amount of Creatinine in the urine for 24hour period.
    
  • 2.) Inulin (use this if they really want to be accurate)– it is a non-natural isomer of fructose, it must be injected into the body. It is freely filtered by the Glomerulus, it is neither secreted nor absorbed by the Tubules, so what is coming out is coming out, this gives the most accurate GFR.
    

     
     

 
 

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