Tubular Mechanism Flashcards
What are the modes of transport mechanisms?
Cellular transport
- Simple diffusion-Net movement represents molecules or ions moving down their electrochemical gradient
- DOESNT require energy - Facilitated diffusion-Molecule or ion moving across a membrane down its concentration gradient, attached to a specific membrane bound protein
- DOESNT require energy - Active transport-Potential mediated transport that uses ATP as a source of energy to move molecules or ions against its electrochemical concentration gradient
Why do we need protein mediated transport?
Protein mediated transport substances cannot readily diffuse across a membrane. Substances like gas and lipid soluble substances readily move across membranes by simple diffusion
How are transporters regulated ?
Except simple diffusion through the lipid bilayer, all transport involves channels and transporters that are regulated by signaling pathways
Contrast simple and facilitated diffusion
As concentration of substance increases then the rate of simple diffusion increases
Once the transporters become saturated, the transport maximum is attained in facilitated transport
Rate of transport depends on
- Concentration of solute
- Number of functioning transporter
Note: the only way to increase the rate of transport after saturation is met, is to increase the number of functional transporters
Contrast primary and active transport
Primary active transport: ATP is consumed directly by transporting protein
Secondary active transport depends indirectly on ATP as a source of energy. e.g. the Na-glucose symporter. This process depends on ATP utilized by the Na+/K-ATPase pump, creating a concentration gradient for sodium, allowing glucose to move up a concentration gradient
-Transporters are primary sites of action for many drugs for the modulation of hypertension and associated renal disorder as we will see in detail in our next slides (on diuretics)
Describe the PCT-Sodium (Na+) Reabsorption
- “filtered load” is the amount of any substance that filters from the glomerulus and enters the Bowman space per unit time (mmol/min or mg/min)
- Aprroximately 2/3 (67%) of the filtered sodium is reabsorbed in the proximal tubule by SGLT and NHE transporter
The basolateral Na/K-ATPase creates the gradient for sodium entry into thr cell and it’s removal from cell back into the blood stream
-Catecholamines and angiotensin II stimulates the basolateral ATPase and thus enhance the fraction of sodium reabsorbed in the proximal tubule
How does the PCT reabsorb water and electrolytes?
Proximal tubules have a high permeability for water and about 2/3 of the filtered water, potassium and about 2/3 of the filtered water, potassium and chloride follow the sodium
The chloride concentration rises slightly through the proximal tubule because of the large percentage of bicarbonate reabsorbed here
Osmotic flow of water in the proximal tubules occurs through tight junctions between the epithelial cells (paracellular pathway), and through the cells themselves (transcellular pathway)
Describe the urine Reabsorption in the PCT
- Nitrogenous wastes are excreted from the body as urea, and, thus plasma blood urea nitrogen (BUN) levels are a useful indicator of renal health and function
- Increased plasma BUN causes Goit and inhibition of urea Reabsorption by the kidneys is a treatment option
As water is reabsorbed from tubule, urea concentration gradient favoring the passive urea Reabsorption of urea paracellularly
What transporters allow for glucose Reabsorption in the PCT?
All filtered glucose is reabsorbed in the PT via secondary active transport linked to sodium. Glucose molecules are recovered from the early PCT by SGLT 2 transporter and from the later PT by the SGLT 1 transporter.
-Glucose uptake by the epithelial cells generates a concentration gradient that drives facilitated diffusion via GLUT 2 and GLUT 1 transporters in the PCT and PST, respectively
What transporters aid in amino acid Reabsorption Hb the proximal tubules?
The Apical surface contains two peptide transporters: PepT1 and PepT2
Both are H+-Peptude cotransport ERC’s that transported dI-and tri peptides
Peptides are degraded inside the cell by proteases and transported to the blood as free amino acids
Defects in these pathway can lead to significant protenuria
The concentration of the glucose, amino acids, etc., should be zero in tubular fluid leaving the PCT
Why is glucose present in the urine in uncontrolled diabetes mellitus?
- Filtration of glucose is proportional to the plasma concentration. Filtration does not saturation
- Reabsorption of glucose is proportional to plasma concentration until the transport maximum (Tm) is reached (saturate)
- Excretion=Filtration-Reabsorption. Glucose excretion is zero until the renal threshold is reached. Renal threshold is plasma concentration at which saturation occurs
The presence of uncovered glucose within the renal tubule lumen causes osmotic diuresis, as polyurua (urine output of >3 L/d)
Describe bicarbonate Reabsorption
-Excreting HCO3^- causes the ECF to become acidic, so the first goal of pH homeostasis is to recover 100% of the filtered HCO3^- load. The PT recovers about 80% of total
Because HCO3^- is anionic, it cannot diffuse freely across membranes.
The PT secretes equal H+ for each HCO3^-. Carbonic anhydrase(CA) converts the H2CO3 and H2O. Both molecules are then recovered by simple diffusion
The PT also actively secretes H+ into the tubule using a H+ pump (V-type H+ ATPase)
Angiotensin II stimulates the Na+/H+ antiproton. Thus, in volume depleted states, the amount of bicarbonate Reabsorption in the PCT increases
Summarize Glomerulotubular balance
- The PCT recaptures two thirds of the filtered sodium, this is reffered to as glomerulotubular balance
- Capturing this sodium helps protect the extracellular volume despite any changes that may occur in GFR
Oncotic pressure of peritubular capillary (pic) is the most important driving force for Reabsorption in the PCT
How do diuretics work?
Diuretic drugs increase urine output by kidney (I.e., promote diuresis) by altering how the kidney handles sodium
Diuretics inhibit sodium Reabsorption—> increase Na+ concentration in lumen—> more water remain in the lumen for excretion
If the kidney excretes more sodium, then water excretion will also increase
Diuretics are used to reduce extracellular fluid volume, especially in diseases associated with edema and hypertension
How is Carbonic anhydrase inhibitor act as a diuretic?d
- Acetazolamide, a carbonic anhydrase (CA) inhibitor, reduces bicarbonate Reabsorption and the activity of the Na+/H+ anti port in the PCT
- Sodium remains in the lumen and therefore water remains in the lumen and excreted in the urine
- Acetazolamide is used in the treatment or prophylaxis of altitude sickness Where urinary bicarbonate excretion is helpful to offset acute respiratory alkalosis; it is also used to reduce intraocular pressure associated with glaucoma
Summarize loop of henle Reabsorption
Consists of 3 functionally distinct segments
Thin descending segment
- Permeable to water (20% of filtered water)
- Relatively impermeable to solute
Thin ascending segment
-impermeable to water
Thick ascending segment
- Impermeable to water
- Solutes transported out (25% of the filtered load of sodium, potassium and chloride absorbed here)
What is the function of thick ascending segment of loop of henle in Reabsorption?
- Na/K-ATPase pump creates a relative Na+ deficiency in the cell—> provides a favorable gradient for the movement of NA+ across the luminal surface into the cell via Na/CL/K cotransporter
- The low intracellular Na+ concentration, also drives the Na/H+ anti port causing H+ secretion and bicarbonate absorption
K+ channel of the luminal membrane causes diffusion of K+ back into lumen—> creates a positive luminal potential—> promotes Na+, Ca2+, and Mg2+ Reabsorption visa paracellular pathway
What are the mechanisms of action of loop diuretics ?
- Loop diuretics block Na/CL/K co-transporter in the luminal membrane —> increase urine output of sodium, chloride, potassium and other electrolytes as well as water
- Explosive increases urine flow occur because this nephron segment normally reabsorbs 20-25% of filtered Na+
Because of their powerful diuretic effect, loop diuretics are particularly useful when rapid diuresis is needed (e.g., pulmonary edema)
Explain early distal tubule Reabsorption
- Early distal tubule reabsorbs Na, CL and Ca. Na/K-ATPase creates a low intracellular concentration, —> NaCl crosses the Apical membrane via a Na/CL- symporter
- Chloride diffuses out of the cell into the renal interstitial fluid through chloride channels in the basolateral membrane.
This segment is impermeable to water—> osmolarity decreases further
The ultrafiltrate in the early distal tubule has the lowest osmolarity of the entire nephron
Explain early distal tubule Reabsorption
- Early distal tubule reabsorbs Na, CL and Ca. Na/K-ATPase creates a low intracellular concentration, —> NaCl crosses the Apical membrane via a Na/CL- symporter
- Chloride diffuses out of the cell into the renal interstitial fluid through chloride channels in the basolateral membrane.
This segment is impermeable to water—> osmolarity decreases further
The ultrafiltrate in the early distal tubule has the lowest osmolarity of the entire nephron
What is the impact of Calbindin in early distal tubule Reabsorption?
-Lumen Ca2+ enters the cell passively through calcium channels, by parathyroid hormone (PTH)
Calcium is actively extruded into the peritubular fluid via Ca2+ -ATPase or 3Na/Ca2+ anti porter
Calcium binding protein “calbindin” facilitates calcium Reabsorption
Calbindin synthesis is increased by the active form of vitamin D, therefore enhance PTH’s action on distal tubule
Mutations of Na-Cl cotransporter —> salt-wasting (Gitslman’s syndrome). Hypocalciuria is a feature of Gitelman’s syndrome and is the result of increased Ca2+ Reabsorption in the distal nephron
What is the mechanism of action of thiazide diuretics?
The thiazides diuretics inhibit the NaCl symporter in the distal tubule and are widely used to treat hypertension and heart failure
Thiazides are less potent than loop diuretics since a lower proportion of the filtered NaCl load is reabsorbed in the distal tubule compared to the loop of henle
Why thiazide diuretics May lead to hypercalcemia?
Inhibiting Na+influx causing DCT epithelial cell hyperpolarization, which increases the electrochemical gradient driving Ca2+ Reabsorption resulting hypercalcemia. Note the difference with loop diuretics which cause hypocalcemia
How does sodium promote Reabsorption by aldosterone?
- Luminal membrane contains sodium channels (ENaC)—> influx of sodium down its concentration gradient (created by Na/K+ ATPase)
- Some chloride does not follow sodium, creating a negative luminal potential causing potassium secretion
Aldosterone activates the mineralcorticoid receptor on these cells, having the folllowing effects:
- Increasing luminal ENaC channels
- Increase ENaC opening time
- Stimulates/augments Na/K+ ATPase
How does ADH impact water Reabsorption?
Principal cells express aquaporins, which are regulated by anti-diuretic hormone (ADH)
- ADH acts on V2 receptors to cause insertion of aquaporins which in turn causes water Reabsorption
- Unlike the cortical collecting tubule, the medullary collecting duct is permeable to urea due to special urea transporters —> facilitates urea diffusion across the luminal and basolateral membranes
What are the potassium-sparing diuretics?
Aldosterone antagonists
- Spironolactone
- Epierenone
Na+ channel blockers
- Amiloride
- Triamterene
What are the functions of intercalates cells in the late distal tubule & Collecting Duct?
- Luminal membrane contains a H+ ATPase , which pumps H+ into the lumen. Most of the H+ is eliminated from the body via buffers, phosphate and ammonia.
- H+ pumped into the lumen binds to phosphate to form deprotonated phosphate, which is poor reabsorbs , thus eliminating H+
H+ can combine with ammonia to form ammonium, which is poorly reabsorbed and is thus excreted. For every H+ excreted by the above buffers, bicarbonate is added to the body (new bicarbonate)
Aldosterone stimulates H+-ATPase of intercalated cells. Thus, excess aldosterone causes Metabolic Alkalosis
Give a general summary of potassium sparing diuretics functioning
-Sodium channel blockers and and the aldosterone antagonists reduce Na+ Reabsorption so K+ secretion diminished —> decreased urinary excretion of K+ and act as K+ -sparring diuretics
K+-sparring agents have a weak diuretic effect because less than 5% of filtered Na+ is reabsorbed at this site
Note: Tumor of adrenal cortex—> primary hyperaldosterone (Conn’s syndrome)—> hypertension (high plasma Na+), hypokalemia (less plasma K+), and metabolic alkalosis (high plasma HCO3^-). Spironolactonecan be helpful in treating patients with Conn’s syndrome
What does aldosterone do?
Increases NaCl, H2O Reabsorption , K+ secretion and H+ secretion in collecting tubule and duct
What does angiotensin II do?
Increases NaCl, H2O Reabsorption, increases H+ secretion in proximal tubule, thick ascending loop of Henle/distal tubule, and collecting tubule
What does ADH do?
Increases H2O Reabsorption in distal tubule/ collecting tubule and duct
What does atrial natriuretic peptide do?
Decreases NaCl Reabsorption in distal tubule/coll3cting tubule and duct
What does parathyroid hormone do?
Decreases PO4 Reabsorption, increases Ca2+ Reabsorption in proximal tubule, thick ascending loop of henle/distal tubule
How do Aldosterone antagonists work?(spironolactone, epierenone)
Inhibit action of aldosterone on tubular receptor, decrease Na+ Reabsorption, and decreases K+ secretion bin collecting tubules
What do Sodium channel blockers do(triamterene, amiloride)?
Block entry Na+ into Na+ channels of luminal membrane, decreases Na+ Reabsorption, and decrease K+ secretion in collecting tubules
What is the site of action of carbonic anhydrase?
Proximal tubules
What is the mechanism of action of osmotic diuretics?
Inhibit water and solute Reabsorption by increasing osmolarity of tubular fluid, mainly in proximal tubules
What is the site of action of thiazide diuretics(hydroxchlorothiazide, chlothalidone)?
Early distal tubules
What is the site of action of Catbonic anhydrase inhibitors(Acetazolamide)?
Proximal tubule
What does inert sugar mannitol do?
The inert sugar mannitol can be used to clinically induce an osmotic diuresis. Mannitol can be helpful in the treatment of patients with head injuries to reduce intracranial pressure by producing a fluid shift out of the brain
