• $V_{\text{te}}=-40mV$$V_{\text{te}} = -40\ mV$ ( lumen with respect to interstitium )

  • this means the lumen is more negative than the interstitial space by $40mV$$40\ mV$

• $V_{\text{apical}}=-25mV$$V_{\text{apical}} = -25\ mV$ ( interacellular with respect to lumen )

  • this means the inside of the enterocyte ( cytosol ) is more negative than lumen by $25mV$$25\ mV$

• $V_{\text{basolateral}}=-65mV$$V_{\text{basolateral}} = -65\ mV$ ( intracellular with respect to the interstitium )

  • this means the inside of the enterocyte ( cytosol ) is more negative than the interstitial fluid by $65mV$$65\ mV$

• Now we have to unpack the wording of these values

• And remember how an electrode / potential recording works

• They put the ground / reference electrode into the extracellular fluid ( lumen )

• They put the recording electrode into the cytosol

• They device reads $-70mV$$-70\ mV$

• You could word this then as $V_{\text{membrane}}=-70mV$$V_\text{membrane} = -70\ mV$ ( intracellular with respect to lumen )

  • so this is how the electrode was placed for $V_{\text{apical}}$$V_{\text{apical}}$ in the question prompt

• For $V_{\text{basolateral}}$$V_{\text{basolateral}}$ in the question prompt , they would of put the recording electrode into the cytosol , and the ground / reference electrode into the intersitial fluid

• You might be tempted to just plug in the values of $V_a$$V_a$ and $V_b$$V_b$ into the formula for $V_{\text{te}}$$V_{\text{te}}$

• But see the trans epithelial current $V_{\text{te}}$$V_{\text{te}}$ is really the voltage across an epithelium

• Words are getting in the way here.

• Just put assign values like this , on either side of the membranes

• Now we can use our formula again , and we can verify the same value as in the question prompt :

• This reminds me of the way the nernst equation written on the card.

• I would just completely ignore the $A$$A$ and $B$$B$ stuff on the card and remember you can write the nernst equation 2 ways :

  • either with a positive 60 , or with a negative 60

  • the negative 60 version is because you flipped the log values

• I personally , always use the $\frac{+60}{Z}$$\frac{+60}{Z}$ version , and remember outside concentration is on top

• if you have a negative ion , chloride for instance , $Z$$Z$ will be negative . but this DOES NOT flip the log !

• Just write it as :

• The Trans-Epithelial Potential Difference (TEPD) across epithelial cells, like those in the kidney and intestines, acts as an electrical gradient that influences the movement of ions and water.

• TEPD represents the electrochemical gradient that governs the movement of ions and water across the epithelial barrier, driven by two forces:

  1. Electrical Gradient: The difference in charge (voltage) across the epithelium.

  2. Concentration Gradient: The difference in ion concentration across the membrane.

• These forces drive ions to move from regions of higher concentration or charge to lower concentration or opposite charge, a fundamental principle of physics often described by the Nernst equation.

• The movement of water is driven osmotically based on solute (primarily ion) concentrations.

Summary: TEPD and Its Role in Ion and Water Transport

1. Na⁺/K⁺ ATPase creates the low intracellular Na⁺ concentration and positive interstitial charge, establishing the TEPD.

2. Na⁺ flows passively into epithelial cells, driven by the Na⁺ gradient and the negative TEPD.

3. Cl⁻ follows Na⁺ to maintain electrical neutrality, assisted by channels like CFTR and antiporters like the Cl⁻/HCO₃⁻ exchanger.

4. K⁺ is recycled via K⁺ channels, helping sustain the TEPD and facilitating ion transport.

5. Water follows the osmotic gradient set up by ion reabsorption, moving passively through aquaporins or paracellularly.

6. Hormonal regulation adjusts these processes, ensuring proper electrolyte and fluid balance in the body.

Kidney vs. Intestines: How TEPD is Used in Different Tissues

• In the intestines, TEPD primarily facilitates nutrient (e.g., glucose) and electrolyte absorption, which indirectly supports water absorption necessary for maintaining fluid balance in the body.

• In the kidney (e.g., proximal tubule, loop of Henle), TEPD drives reabsorption of electrolytes and water crucial for urine concentration and volume regulation.

Students can describe serial processing of meal components by the gastrointestinal organ system. Students can describe epithelial flow pathways supporting transepithelial absorption and secretion.

• we don't do it all at once

• each component specializes

• makes it easier for the next section

Process of Saliva Secretion and Osmotic Forces Leading to Cell Lysis:

1. Primary Secretion (Isotonic Fluid Production):

   • Acinar cells in salivary glands produce an initial secretion.

   • This primary fluid is isotonic to plasma, meaning it has a similar concentration of solutes like sodium (Na⁺) and chloride (Cl⁻).

   • Water follows the ions into the lumen through osmosis, maintaining an equal solute concentration inside the lumen and the surrounding cells.

2. Ductal Modification of Saliva (Hypotonic Fluid):

   • The isotonic fluid moves from the acinar cells into the ducts of the salivary glands.

   • In the ducts, Na⁺ and Cl⁻ are reabsorbed, while K⁺ and HCO₃⁻ are secreted into the saliva.

   • The ducts are impermeable to water, so although ions are reabsorbed, water stays in the saliva.

   • This process causes the final saliva to become hypotonic (lower in solute concentration compared to plasma).

3. Contact with Cells (Osmotic Gradient Creation):

   • When this hypotonic saliva comes into contact with cells, like bacteria, an osmotic gradient is established.

   • The inside of the bacterial cell has a higher solute concentration compared to the hypotonic saliva outside.

4. Osmotic Water Influx:

   • Water flows into the bacterial cells by osmosis because water moves from areas of lower solute concentration (hypotonic saliva) to areas of higher solute concentration (inside the bacterial cell).

5. Cell Swelling and Lysis:

   • As water enters the bacterial cell, the cell swells.

   • If the bacterial cell membrane or wall cannot withstand the increased internal pressure from the water influx, the cell can lyse (burst) due to the osmotic pressure.

Gastric Secretions

• Acid secretion

• Parietal Cells

  • Intrinsic factor

    • helps absorb B12

• Chief Cells

  • release pepsin

Microbiome

• cellulase

Pancreas

• digests everything

  • most important digestive organ

• amylases , peptidases , lipases

• dumps bi-carb everywhere to buffer stomach acid

  • carbonic anhydrase system

  • keeps saying that maybe metabolism isn't enough carbon to generate the amount of CO2 you need to run this system ?

Liver

• also bicarb

• and bile acids

Passive Nutrient Absorption in Brush Boarder Membrane

• di-saccharides

• lactose

• sucrose

• proteins

• amino acids

• fats

• fluids = bulk of reabsorption happens distally

• nutrient reabsorption happens proximally in intestine

Misc

• peristalsis mixes and moves it along

• control is neural and hormonal

  • cephalic phase - sensory

    • salivary , gastric , and pancreatic secretions

  • gastric phase - enteroendocrine cells

    • g-cells produce gastrin = stimulates H+ screation and pepsinogen release

    • s-cells produce secretin = stimulates pancreatic bicarbonate secretion

    • i-cells produce CCK = stimulates enzyme release from acinar cells

    • l-cells produce peptide-YY = satiety

Students can describe cellular mechanisms for solute and water absorption and secretion.

• Absorption: Nutrients and ions are absorbed primarily in the small intestine through both cellular pathways (via transport proteins) and paracellular pathways (between cells). Na⁺/K⁺-ATPase creates a gradient that drives the uptake of nutrients and water.

• Secretion: Cells in the GI tract also secrete electrolytes and enzymes necessary for digestion.

  • For example, chloride is secreted through channels like CFTR , facilitating water movement by osmosis

• Solute absorption involves active transport mechanisms like the Na⁺/K⁺-ATPase , which maintains a low intracellular Na⁺ concentration, allowing Na⁺ and nutrients to enter cells via co-transporters

• Water follows solutes passively through aquaporins or paracellular routes driven by osmotic gradients established by solute transport

Students can predict steady-state cellular conductive properties during absorption and secretion.

• In steady-state conditions, the membrane potential and ion gradients ( such as Na⁺ and K⁺ ) are maintained by the Na⁺/K⁺ pump, ensuring that absorption ( e.g., of Na⁺ ) is balanced with secretion ( e.g., of Cl⁻ ).

• The trans-epithelial potential difference ( TEPD ) remains stable due to balanced ion flows

Students can predict maximal concentration and electrical gradients attainable by cellular solute transport mechanisms.

• The maximal gradient is set by the electrochemical driving force determined by ion concentrations and the TEPD. For instance, the Na⁺/K⁺-ATPase can maintain intracellular Na⁺ at low levels, allowing high rates of nutrient co-transport

• Use the table

  • write out driving force equations for each ion involved

  • multiply across based on how many ions are flowing $\left(n\right)$$\left(\ n \ \right)$

  • add up the absolute value of all membrane potentials

  • convert to energy using faraday constant

Students can predict physiological outcomes to changes in dietary nutrients.

• An increase in dietary fats triggers the release of bile acids from the liver for emulsification , while proteins and carbohydrates stimulate pancreatic enzyme release.

• Changes in dietary fiber affect water retention and transit times in the colon, influencing stool consistency

Students can describe endocrine/neural control of digestion and absorption of nutrients.

• The Cephalic Phase involves neural control via the vagus nerve, stimulating saliva, gastric acid, and enzyme secretion in anticipation of food.

• The Gastric Phase is regulated by gastrin, which increases HCl production in response to stomach distention and proteins.

• The Intestinal Phase uses hormones like secretin and cholecystokinin ( CCK ) to regulate bicarbonate and enzyme secretion , coordinating digestion

Topic 1

• Kidney = multi-stage filter

• TALH = thick ascending limb of henle

• Cell Swelling avoided by :

  1. sodium-potassium-ATPase

     • creates initial ion gradient

  2. potassium leak channels

     • maintain a negative cell potential $E_m$$E_m$

  • Both #1 and #2 items together make sodium and chloride concentrations high outside of the cell

• There is a pressure drop in capillaries , from arterial end to the venous end

• Hydrostatic Pressure (P): This is the pressure exerted by the fluid inside the blood vessels. It tends to push water and solutes out of the capillary into the interstitial space (filtration).

• Oncotic (or Colloid Osmotic) Pressure (π): This is the osmotic pressure exerted by plasma proteins (mainly albumin), which tends to pull water back into the capillary (absorption).

• Pressure Differences from Arterial to Venous End:

  • Arterial End: The hydrostatic pressure is higher at the arterial end of the capillary (typically around 35 mmHg). This high pressure pushes fluid out of the capillary into the surrounding tissue (filtration).

  • Venous End: As blood moves through the capillary, hydrostatic pressure drops significantly (to about 15 mmHg). Meanwhile, oncotic pressure (around 25 mmHg) remains relatively constant throughout the capillary. By the time blood reaches the venous end, the oncotic pressure becomes greater than the hydrostatic pressure, creating a net pull of fluid back into the capillary (absorption)

• From a physics perspective, this pressure drop is analogous to energy dissipation in a fluid flow system. The movement of blood through the narrow capillaries causes a loss of kinetic energy (due to resistance), which manifests as a drop in pressure. The oncotic pressure, which is relatively constant due to the steady presence of proteins, eventually overtakes the diminishing hydrostatic pressure, leading to a reversal of fluid movement back into the vessel.

Topic 2

• Paracellular Pathway = Filtration

• Cellular Pathway = Absorption

• Nephron :

  • glomerulus = filter

  • proximal tubule = absorption of fluid

  • diluting segment = selective salt absorption

  • distal tubule = selective water ( or salt ) absorption

Topic 3

• Glomerulus :

  • podocytes support against pressure

  • has fenestration pores

  • prevents blood cells and plasma proteins from entering nephron

  • afferent arteriole = in flow

  • efferent arteriole = exit flow

• Macula Densa = boundary between proximal and distal sections

• There are ways the body can autonomically control / constrict both the afferent and efferent arterioles

  • myogenic response ( Bayliss reflex )

  • maintains steady hydrostatic pressure of 60 mmHg

• The glomerulus can also sense if there is high amounts of NaCl in the lumen , or just high osmolarity in general

  • it will decrease GFR

  • renin ?

Topic 4

• A good marker to measure GFR :

  • something filtered , but not re-absorbed , and not secreted

• You can use inulin or creatinine

• $U_x$$U_x$ = concentration of substance X in urine

• $P_x$$P_x$ = concentration of substance X in plasma

• $K_{\text{fil}}$$K_{\text{fil}}$ = filtration coefficient

• $U_{\text{PAH}}$$U_{\text{PAH}}$ = concentration of para-aminohippuric acid ( PAH ) in urine

• UFR = urine flow rate

• $P_{\text{PAH}}$$P_{\text{PAH}}$ = concentration of PAH in plasma

• $C_{\text{PAH}}$$C_{\text{PAH}}$ = total clearance of PAH

• $U_x$$U_x$ = concentration of substance X , in the urine

• this is equal to 1 for creatine , because creatinine is freely filtered and NOT reabsorbed or secreted by the kidneys

• for water though :

Topic 5

• 2/3 of all the filtrate is re-absorbed in the proximal tubule

  • basically , reabsorb all the fluid

  • reabsorb all the valuable things

    • Na , Cl , HCO3 , K , Ca , Mg , PO4 , water ( isotonic ) , glucose , amino acids

  • leave everything undesirable trapped in the lumen of the nephron

    • products of metabolism , organic cations , anions

• its a convoluted tubule , help with absorption ( stirring )

• On the inverse graph thing ,

  • inulin concentration is on the Y-axis ,

    • it increases in concentration as you go vertically

  • but simultaneously it shows the concentration of water as being the inverse

  • this is just saying that as we go through the nephron , we are increasing the concentration of inulin ( our perfect GFR recording molecule , because it doesn't get re-absorbed or secreted , it just gets filtered straight through to the collecting duct ).

    • ok and as expected , by the time we get to the collecting duct , we are left with virtually zero water left ( 1 / 1000 ) because it has all be re-absorbed

• Driving Forces for Absorption :

  • Capillaries :

    • hydrostatic

    • osmotitc

  • Nephron :

    • osmotic

• Bicarbonate Absorption ;

  • Apical = Sodium \ Proton Exchanger

  • Basolateral = Sodium \ Bi-Carb Co-Transporter

• To get trans epithelial flow , you need different transporter types on apical vs basolateral sides

  • if they were the same , there would be no gradient

• Bicarb gets concentrated as we absorb all of the water

• absorbed = filtered - secreted

Topic 6

• Proximal Nephron = most absorption

• Distal Nephron = fine adjustment

• A vs B Type Distal Tubule Cells

Topic 7

• How does the structure of the kidney allow us to re-absorb water against its concentration gradient ?

• No aquaporins in ascending limb

• Counter Current Exchange = down , and then back up ( hairpin movement )

  • maintains gradient

• The ascending limb does have Na \ K \ 2Cl co transporters at the top

  • at the last possible moment , we throw away NaCl into the intermedullary space

• NaCl enters outer medulla from TALH

• Urea enters inner medulla from IMCD

• We need capillaries to receive fluid , and the cells need oxygen.

  • so capillaries do counter-current exchange as well

• Proximal Tubule = continual absorption

• Thin Descending Limb = continual absoprtion

• Late Distal Tubule = low H2O permeability

• ADH = causes distal nephron / collecting ducts to insert aquaporins

  • allows for water reabsorption ( dehydrated )

• Glomerulus has "compact" osmotic gradient , due to its shape

• The Proximal Tubule has a large-scale osmotic gradient

• Free Water Clearance ?

• ADH / Vasopressin :

  • upregulates aquaporin expression in distal nephron and collecting ducts

  • increases urea permeability for inner medullary collecting duct

  • stimulates NaCl absorption in thick ascending limb

  • increases blood flow to juxtamedullary glomeruli

    • dilation = increased flow rate

• Diabetes Insipidus = lack of ADH release ➡️ urinate tons of water

Topic 8

• Aldosterone :

  • $\downarrow$$\downarrow$ Pressure ➡️ $\uparrow$$\uparrow$ renin ➡️ $\uparrow$$\uparrow$ aldosterone ➡️ $\uparrow$$\uparrow$ Sodium Channels ➡️ $\uparrow$$\uparrow$ Sodium Absorption

• Huge ability to get rid of potassium

  • Because , aldosterone increases sodium absorption ,

    • this also drives potassium secretion

• Intercalcated cells secrete acid ,

  • this turns on potassium pumps to re-absorb potassium

Topic 9

• Breath Faster = export CO2

• If we know how many cations there are , then there has to be a similar amount of anions if our solution neutral

  • aka , anion gap

• There are a lot of acidic ( anions ) byproducts from normal metabolism

• 93% of filtered bicarbonate is absorbed in proximal tubule

• We have to maintain the $\frac{C{O}_2}{HC{O}_3^{-}}$$\frac{CO_2}{HCO_3^-}$ ratio

  • acid = CO2

  • base = BiCarb

• "New" BiCarb

  • at the end of proximal tubule , 1/2 the protons are on phosphates now

• Ammonia's pKa = 9.3

  • its a very strong base , so by definition , its a much better proton trap

• Transcytosis of Protons = protons from sulfate are moved to bicarbonate

• Intercalcated Cells and Bacteria don't use Na \ K \ ATPase to maintain negative intracellular state

  • they use proton pumps instead

  • this allows the nephron to build up a much stronger gradient

    • more efficient

• If you are willing to rip apart amino acids , you can get rid of as much acid as you want.

  • by-products of amino acid degradation create high amount of NH3

• Ammonia = same size as potassium

  • it can travel through potassium channels

• Example , Adaptation to Altitude ( acute effects )

  1. Altitude Increase

  2. Less Oxygen

  3. Breath Faster

  4. Offload CO2

  5. Enter into Alkalosis ( basic ) state

  6. Kidneys export more bicarb now

     • this happens in proximal tubule though

     • and since you are loosing osmoles ( not reabsorbing bicarbonate )

       • you don't reabsorb as much water now

       • so now you are also dehydrated

• Absorbed = filtered - excreted

• Volume Contracted = excrete more bicarbonate

• Volume Expanded = stop secreting bicarb

• Vomiting = loosing volume and acid , makes you enter into alkalosis state

• Diarrhea = loosing volume and base , makes you enter into acidic state

• RAAS System

• Aldosterone

Students can describe glomerular filtration in the kidney.

• Glomerular filtration occurs in the nephron’s glomerulus, where blood is filtered into the renal tubule.

• The filtration barrier consists of capillary endothelium, the basal lamina, and podocyte slit diaphragms.

• Plasma is filtered through these layers, forming the ultrafiltrate that excludes blood cells and plasma proteins due to size and charge barriers.

Students can predict changes in glomerular filtration rate due to arteriolar constriction.

• The GFR depends on the pressure in the glomerular capillaries, which is controlled by the resistance of the afferent and efferent arterioles.

• Constriction of the afferent arteriole reduces GFR by decreasing renal blood flow and glomerular pressure.

• Constriction of the efferent arteriole initially increases GFR due to increased capillary pressure but can decrease GFR if severe constriction occurs

Students can calculate glomerular filtration rate and renal clearance.

• GFR can be calculated using the formula:

• Where $U_x$$U_x$ is the urine concentration of a marker ( e.g., inulin ) , $UFR$$UFR$ is the urine flow rate, and $P_x$$P_x$ is the plasma concentration of the marker. The marker should ideally be filtered but neither reabsorbed nor secreted. Creatinine is often used for estimating GFR as it is primarily filtered

   

• The renal clearance of a substance ( $C_x$$C_x$ ) is defined as the volume of plasma that is completely cleared of a particular substance per unit time. It can be calculated using the basically the same formula:

• Renal clearance measures the effectiveness of the kidneys in removing a substance from the blood.

Students can describe renal tubule solute and water flow based on cellular transport mechanisms.

• Different segments of the nephron utilize distinct transport mechanisms for solute and water flow.

• For instance, in the proximal tubule, Na+ is absorbed with glucose and other solutes via Na+/glucose cotransporters.

• Water follows passively due to the osmotic gradient.

• In the loop of Henle , active NaCl transport occurs in the thick ascending limb ( TALH ) , which is water-impermeable, contributing to the dilution of the tubular fluid

Students can describe the morphological basis of tubule fluid concentration during high and low water intake.

• During high water intake ( diuresis ) , water permeability in the distal tubule and collecting duct is low , producing dilute urine.

• In contrast , during water scarcity ( antidiuresis ) , antidiuretic hormone ( ADH ) increases the water permeability of these segments , allowing for concentrated urine as water is reabsorbed.

• The loop of Henle's countercurrent multiplication and urea recycling are critical in establishing the high osmolarity in the renal medulla necessary for this concentration process

Students can describe hormonal control of solute and water transport.

• Hormones like ADH and aldosterone regulate water and solute transport.

• ADH increases water reabsorption by inserting aquaporins in the collecting duct.

• Aldosterone enhances Na+ reabsorption and K+ secretion in the distal tubule and collecting duct by increasing the number of Na+ channels and Na+/K+ pumps

Students can predict renal tubule response to perturbations in systemic acid/base balance.

• The renal system compensates for systemic pH imbalances.

• In acidosis, the kidney increases H+ secretion and promotes bicarbonate reabsorption through the action of intercalated cells ( Type A ).

• Conversely, during alkalosis, Type B intercalated cells increase bicarbonate secretion and reduce its reabsorption

Misc

• bulk of reabsorption in the intestine happens distally

  • this is opposite of the kidney nephron , where the bulk of water is reabsorped in the proximal tubule

• most nutrient absorption occurs in the proximal intestine