Transport of sodium and chloride

Question 1

What is the paracellular pathway for Na⁺ reabsorption?

Answer 1

Definition: Na⁺ moves between cells through the tight junctions without entering the cells.
Driven by: Electrochemical gradient (passive transport).
Locations: Prominent in proximal tubules of the kidney.
Key Point: Na⁺ is reabsorbed along with water, contributing to the bulk reabsorption of sodium.

Question 2

What is the transcellular pathway for Na⁺ reabsorption?

Answer 2

Definition: Na⁺ moves through the cells, crossing both the apical (luminal) and basolateral membranes.
Mechanism:
Na⁺ enters the cell via Na⁺ channels or transporters on the apical membrane.
Na⁺ exits the cell at the basolateral membrane through Na⁺/K⁺ ATPase pumps.
Locations: Occurs in distal nephron (e.g., distal tubules, collecting ducts).
Energy: Requires ATP (active transport).

Question 3

Describe Na+ absorption in the proximal tubule

Answer 3

~60-70% of Na+ is reabsorbed through transcellular and paracellular pathways. Na+ transport is linked with other solutes via Na+-coupled transporters such as SGLT and sodium-amino acid transporter

Question 4

What is renin?

Answer 4

The enzyme which cleaves angiotensin I from angiotensinogen

Question 5

How does renin ensure the control of vascular resistance, blood pressure, blood volume and Na+ and K+ balance?

Answer 5

Angiotensin I is converted to angiotensin II via angiotensin converting enzyme (ACE) and acts on AT1 receptors in vascular smooth muscle to cause vasoconstriction, and in the adrenal cortex to release aldosterone hence controlling vascular resistance.

Question 6

Why is the proximal-distal tubule leaky?

Answer 6

Allows permeability to water and ions and permits flow in either direction. This prevents the build-up of large concentration gradients

Question 7

What is the most important mechanism of Na+ entry into proximal tubular cells?

Answer 7

By Na+/H+ exchange. Na+ is reabsorbed from tubular fluid into the cytoplasm of proximal tubular cells in exchange for cytoplasmic H+. It is then transported out of the cells into the interstitium by a Na+-K+-ATPase (sodium pump) in the basolateral membrane.

Question 8

Where is bicarbonate absorbed?

Answer 8

Bicarbonate is normally completely reabsorbed in the proximal tubule. This is achieved by combination with protons, yielding carbonic acid, which dissociates to form carbon dioxide and water – a reaction catalysed by carbonic anhydrase present in the lumenal brush border of the proximal tubule cells – followed by passive reabsorption of the dissolved carbon dioxide.

Question 9

Where is filtered glucose absorbed?

Answer 9

Proximal tubule

Question 10

By which transporter is glucose absorbed in the proximal tubule and how?

Answer 10

Glucose is reabsorbed in the proximal tubule. It is co-transported with sodium ions by an SGLT - sodium/glucose cotransporter.

Question 11

How much glucose is reabsorbed?

Answer 11

80-90%

Question 12

What drugs inhibit the SGLT co-transporter?

Answer 12

Gliflozins; empagliflozin, dapagliflozin, cangliflozin.

Question 13

State the difference between SGLT1 and SGLT2.

Answer 13

SGLT2 is expressed early in the proximal tubule and absorbs the majority of filtered glucose. SGLT1 is expressed further along the proximal tubule and accounts for the filtration of the remaining glucose.

Question 14

What does NaCl do in the thick ascending limb (TAL)?

Answer 14

NaCl is actively reabsorbed causing hypertonicity in the interstitium.

Question 15

What drugs inhibit the proximal tubule?

Answer 15

Carbonic anhydrase inhibitors

Question 16

What drugs inhibit the Henle loop?

Answer 16

Loop diuretics

Question 17

Give an example of loop diuretics

Answer 17

Furosemide, bumetanide, torasemide

Question 18

What drugs inhibit the distal convoluted tubule?

Answer 18

Thiazides

Question 19

Give examples of thiazides.

Answer 19

Indapamide, metolazone and chlortalidone

Question 20

What drugs/hormones inhibit the collecting ducts?

Answer 20

ADH(vasopressin), amiloride, triamterene, aldosterone

Question 21

How do ions move into the thick ascending limb?

Answer 21

Across the apical membrane by the Na+/K+/2Cl- cotransporter

Question 22

How is the movement of ions into the TAL?

Answer 22

By the concentration gradient of Na+ generated by Na+/K+/ATPase in the basolateral membrane

Question 23

How is NaCl transported in the distal tubule?

Answer 23

Na+/K+/ATPase

Question 24

What is the role of TRPV5 in distal tubular cells?

Answer 24

The TRPV5 channel on the apical surface (lumen side) of distal tubular cells is permeable to Ca²⁺, allowing calcium to enter the cells from the filtrate.

Question 25

How is Ca²⁺ reabsorbed on the basolateral surface of distal tubular cells, and which hormones regulate this process?

Answer 25

On the basolateral surface, Ca²⁺ is reabsorbed via an active Na⁺/Ca²⁺ transporter and a Na⁺/Ca²⁺ antiporter, which is driven by the gradient created by the ATP-dependent Na⁺/K⁺ pump. Parathormone (PTH) and calcitriol regulate Ca²⁺ reabsorption by increasing the synthesis of these transporters and promoting Ca²⁺ reabsorption while increasing phosphate excretion.

Question 26

Do the junctions in the collecting tubules/ducts allows water and ions to permeate?

Answer 26

No

Question 27

How are NaCl and water absorption regulated in the collecting ducts/tubules

Answer 27

In this segment of the nephron, the movement of ions and water is under independent hormonal control. Aldosterone regulates the absorption of NaCl, while antidiuretic hormone (ADH) controls the absorption of water.

Question 28

How does aldosterone promote Na+ reabsorption?

Answer 28

Up-regulating epithelial sodium channels in the collecting duct, increasing apical membrane permeability and hence by action on membrane aldosterone receptors. Delayed effects, via nuclear receptors, direct the synthesis of a specific protein mediator up-regulating and activating the basolateral Na+/K+ pump, which pumps three sodium ions out of the cell, into the interstitial fluid and two potassium ions into the cell from the interstitial fluid and stimulates synthesis of the epithelial sodium ion channel in addition to its rapid effect via the membrane receptor mentioned earlier.

Question 29

Which pituitary is ADH secreted by?

Answer 29

Posterior

Question 30

How does ADH regulate water absorption in the nephron?

Answer 30

ADH increases the expression of aquaporin-2 (AQP2) channels on the apical membrane of collecting duct cells, allowing water to move from the lumen (urine) into the cell. Water then exits through aquaporin-3 (AQP3) and aquaporin-4 (AQP4) channels on the basolateral membrane into the bloodstream.

Question 31

How are epithelial Na⁺ channels (ENaC) regulated?

Answer 31

By aldosterone

Question 32

What inhibits ENaC channels?

Answer 32

Amiloride and triamterene

Question 33

When is K+ lost?

Answer 33

When more Na+ reaches the collecting duct, as occurs with any diuretic acting proximal to the collecting duct and when Na+ reabsorption in the collecting duct is increased directly

Question 34

When is K+ retained?

Answer 34

Na+ reabsorption in the collecting duct is decreased, for example by amiloride or triamterene, which block the sodium channel in this part of the nephron, or spironolactone, eplerenone, or finerenone, which antagonise aldosterone.

Question 35

What is the main use of diuretics?

Answer 35

Increase excretion of sodium and water

Question 36

Where do loop diuretics act?

Answer 36

TAL

Question 37

How do loop diuretics act?

Answer 37

They inhibit the Na+/K+/2Cl- cotransporter the luminal membrane by increasing the Na+ delivery to the distal nephron causing loss of H+ and K+

Question 38

When are loop diuretics given/symptoms?

Answer 38

Hypertension, hypercalcemia, pulmonary oedema, chronic heart failure, renal failure

Question 39

Side effects of loop diuretics?

Answer 39

Hypotension, hypokalemia, hypovolemia,

Question 40

What is the mechanism of action of thiazides in the kidney?

Answer 40

Thiazides bind the Cl− site of the distal tubular Na⁺/Cl⁻ co-transporter, inhibiting its action. This causes natriuresis, leading to the loss of sodium and chloride ions in the urine. The resulting contraction in blood volume stimulates renin secretion, leading to angiotensin formation and aldosterone secretion

Question 41

How do thiazides impact calcium excretion and why might this be beneficial?

Answer 41

Thiazides reduce Ca²⁺ excretion, which can be advantageous for older patients at risk of osteoporosis. This effect may favor the use of thiazides over loop diuretics for such individuals.

Question 42

Name the clinical uses of thiazides.

Answer 42

Hypertension, mild heart failure, severe resistant oedema, nephrogenic diabetes insipidus

Question 43

Name aldosterone antagonist drugs.

Answer 43

Spironolactone, eplrenone, finenerone

Question 44

Why do spironolactone, eplerenone, and finerenone have limited diuretic action when used alone?

Answer 44

Spironolactone, eplerenone, and finerenone have limited diuretic action alone because the distal Na⁺/K⁺ exchange, the site where they act, accounts for only 2% of filtered Na⁺ reabsorption.

Question 45

What therapeutic effects do spironolactone, eplerenone, and finerenone have beyond diuresis?

Answer 45

These drugs have marked antihypertensive effects, prolong survival in selected patients with heart failure, and finerenone helps preserve renal function and reduce cardiovascular death in type 2 diabetic patients with chronic kidney disease (CKD).

Question 46

How do spironolactone, eplerenone, and finerenone prevent hypokalaemia?

Answer 46

These drugs prevent hypokalaemia when combined with loop diuretics or thiazides by competing with aldosterone for the intracellular mineralocorticoid receptor, inhibiting distal Na⁺ retention and K⁺ secretion.

Question 47

What is the mechanism of action of spironolactone, eplerenone, and finerenone?

Answer 47

They compete with aldosterone for the intracellular mineralocorticoid receptor, thereby inhibiting distal Na⁺ retention and K⁺ secretion, reducing blood pressure and improving outcomes in heart failure and CKD.

Question 48

Why are potassium-sparing diuretics used with K⁺-losing diuretics like loop or thiazide diuretics?

Answer 48

Potassium-sparing diuretics are used with K⁺-losing diuretics to prevent potassium loss, which is particularly hazardous in patients requiring digoxin or amiodarone, as hypokalaemia increases the risk of toxicity.

Question 49

In which conditions is spironolactone or eplerenone used to improve patient outcomes?

Answer 49

Heart failure to improve survival Primary hyperaldosteronism (Conn’s syndrome) Resistant essential hypertension, especially low-renin hypertension Secondary hyperaldosteronism caused by hepatic cirrhosis with ascites.