Parathyroid hormone (PTH) increases renal phosphate excretion by inhibiting its reabsorption in the proximal convoluted tubule. Which transporter is directly blocked by PTH signaling?

Explanation

## PTH-Mediated Phosphaturia **Key Point:** PTH causes phosphaturia by directly reducing the expression and activity of the Na⁺-phosphate cotransporter NaPi-IIa in the proximal tubule brush border. ### Mechanism of PTH-Induced Phosphate Wasting PTH binds to PTH1R on proximal tubule cells and triggers: 1. **Activation of PKA pathway** via cAMP 2. **Phosphorylation and internalization of NaPi-IIa** from the apical membrane 3. **Degradation of NaPi-IIa** protein via ubiquitin-proteasome pathway 4. **Decreased proximal tubule reabsorption** of filtered phosphate 5. **Increased urinary phosphate excretion** (phosphaturia) **High-Yield:** NaPi-IIa is the major phosphate transporter in the proximal tubule. PTH-induced removal of NaPi-IIa from the membrane is the **primary mechanism** of phosphaturia — not a change in GFR or passive loss. ### Physiologic Significance **Mnemonic:** **PHOS-PATE** — **P**TH **H**yperphosphaturia **O**ccurs **S**econdary to **P**roximal tubule **A**ction on **T**ransporter **E**xpression. This phosphate-wasting effect of PTH: - Lowers serum phosphate (which would otherwise inhibit 1,25-dihydroxyvitamin D synthesis) - Allows 1α-hydroxylase to remain active, promoting vitamin D activation - Enhances intestinal calcium absorption - Completes the PTH-mediated hypercalcemic response **Clinical Pearl:** In chronic kidney disease, loss of PTH responsiveness (secondary hyperparathyroidism) leads to phosphate retention, hyperphosphatemia, and suppression of 1,25-dihydroxyvitamin D — a vicious cycle. | Transporter | Location | Function | PTH Effect | |-------------|----------|----------|------------| | **NaPi-IIa** | **Proximal tubule brush border** | **Phosphate reabsorption** | **Inhibited (internalized)** | | NCX | Basolateral membrane | Na⁺/Ca²⁺ exchange | Not directly targeted | | AQP-2 | Collecting duct | Water reabsorption | Stimulated (ADH-mediated) | | Na⁺-K⁺-ATPase | Basolateral membrane | Ion pump | Not directly targeted | **Warning:** Do not confuse NaPi-IIa inhibition with decreased GFR. PTH does not reduce glomerular filtration of phosphate; it reduces **reabsorption** of already-filtered phosphate.