Questions: Proximal Tubule Reabsorption and Secretion

Question 1

A toxin selectively and completely inhibits Na⁺/K⁺-ATPase in proximal tubule cells. Which consequence is most directly predicted by understanding the reabsorption mechanism?

• A. Glucose and amino acids accumulate inside tubule cells because they can no longer exit into the blood
• B. Glucose and amino acids remain in the tubular filtrate and are lost in urine, because the sodium gradient driving cotransporter uptake collapses
• C. Water reabsorption increases to compensate for the loss of solute transport
• D. Secretion of drugs and organic acids into the lumen increases because the apical transporters are now unregulated

Answer: (B)

The Na⁺/K⁺-ATPase is the ultimate energy source for all Na⁺-coupled transport. By maintaining low intracellular Na⁺, it creates the gradient that SGLT2, SGLT1, and amino acid cotransporters harness to pull glucose and amino acids from the lumen into the cell. Block the ATPase, and intracellular Na⁺ rises, the gradient collapses, and cotransporters stop working. Glucose and amino acids that would normally be reabsorbed remain in the filtrate and appear in urine (glucosuria, aminoaciduria). Option A confuses direction — the ATPase powers uptake from lumen to cell, not from cell to blood.

Question 2

A patient takes penicillin, which is more than 60% protein-bound in plasma. Despite this, the drug is rapidly cleared by the kidneys. What mechanism explains this?

• A. Protein-bound penicillin is freely filtered at the glomerulus because the glomerular barrier is not selective for proteins
• B. Penicillin displaces from albumin inside the glomerular capillary and the free fraction is filtered
• C. Proximal tubule secretion via organic anion transporters picks up protein-bound penicillin from peritubular blood and delivers it to the tubular lumen for excretion
• D. Penicillin is reabsorbed and then secreted in a recycling process that concentrates it in the filtrate

Answer: (C)

Protein-bound drugs cannot cross the glomerular filtration barrier — only free (unbound) drug is filtered. Tubular secretion provides an alternative elimination route: OATs on the basolateral membrane of proximal tubule cells actively transport organic anions (including penicillin) from peritubular blood into the cell, and apical transporters then dump them into the lumen. This is physiologically important because it allows elimination of substances that filtration alone cannot handle. It is also clinically relevant — probenecid blocks this OAT-mediated secretion and was historically used to prolong penicillin's half-life.

Question 3

The transport of glucose from the tubular lumen into proximal tubule cells is driven by the sodium concentration gradient rather than directly by ATP hydrolysis.

• T. True
• F. False

Answer: True

SGLT2 and SGLT1 are cotransporters that move glucose into the cell by coupling it to the movement of Na⁺ down its concentration gradient. The ATP is consumed one step removed, by the Na⁺/K⁺-ATPase that maintains the low intracellular Na⁺. The cotransporter itself uses no ATP directly — it is 'secondary active transport.' This distinction matters clinically: SGLT2 inhibitors (gliflozins) block glucose reabsorption without directly affecting the ATPase, allowing glucose to spill into urine as a blood sugar–lowering mechanism.

Question 4

The proximal tubule generates a large osmotic gradient along its length by reabsorbing solutes faster than water, concentrating the remaining filtrate.

• T. True
• F. False

Answer: False

The proximal tubule reabsorbs solutes and water in nearly equal proportions, so the fluid leaving the proximal tubule remains approximately isosmotic with plasma. Water follows solutes through aquaporin-1 channels by osmosis so efficiently that no significant concentration gradient builds up. Urine concentration happens much later, in the loop of Henle and collecting duct — the proximal tubule's job is volume recovery (reclaiming ~65% of filtered water), not concentration.

Question 5

Explain why the Na⁺/K⁺-ATPase is considered the 'engine' of proximal tubule reabsorption, even though it does not directly transport glucose or amino acids.

Model answer: The Na⁺/K⁺-ATPase on the basolateral membrane pumps Na⁺ out of tubule cells into the interstitium, keeping intracellular Na⁺ concentration very low. This creates a steep electrochemical gradient for Na⁺ across the apical membrane. Cotransporters like SGLT2 (for glucose) and sodium-amino acid cotransporters exploit this gradient: Na⁺ flows downhill into the cell, and these cotransporters harness that energy to carry glucose or amino acids uphill against their own concentration gradients. The ATPase is the ultimate energy source — without it, the Na⁺ gradient collapses, and all Na⁺-coupled cotransport stops even though those cotransporters themselves use no ATP directly.

This hierarchy — ATPase → Na⁺ gradient → cotransporters — illustrates secondary active transport. It is a common energetic architecture in biology wherever cells need to concentrate substances against their gradients without each transporter needing its own ATP supply.