Pioglitazone (thiazolidinedione) causes fluid retention and weight gain as major adverse effects. The molecular mechanism linking PPAR-gamma activation to sodium and water retention is:
- A PPAR-gamma activation in collecting duct increases expression of SGK1 which phosphorylates and activates ENaC, increasing sodium reabsorption ✓
- B Pioglitazone directly activates aldosterone receptors in the distal nephron
- C PPAR-gamma activation increases renal aquaporin-2 expression via VEGF upregulation
- D Insulin sensitization increases adiponectin, which promotes renal sodium retention through AMPK pathways
Correct answer: A. PPAR-gamma activation in collecting duct increases expression of SGK1 which phosphorylates and activates ENaC, increasing sodium reabsorption
Explanation
PPAR-gamma nuclear receptors, when activated by thiazolidinediones, upregulate expression of serum and glucocorticoid-regulated kinase 1 (SGK1) in renal collecting duct principal cells. SGK1 phosphorylates and activates the epithelial sodium channel (ENaC), increasing Na+ reabsorption. This leads to sodium and water retention, edema, and weight gain. This mechanism is also responsible for the increased risk of heart failure exacerbation seen with thiazolidinediones. Pioglitazone/rosiglitazone are therefore contraindicated in NYHA class III/IV heart failure.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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