Sodium-dependent phosphate cotransporter 2A (NaPi-IIa) and Sodium-dependent phosphate cotransporter 2C (NaPi-IIc) (NaPi-IIa and NaPi-IIc)

The renal sodium-phosphate cotransporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) are the primary mediators of inorganic phosphate reabsorption in the kidney's proximal tubule [2, 4, 10]. Located on the apical brush border membrane, these transporters utilize the sodium electrochemical gradient to move phosphate from the tubular lumen into the epithelial cells [14, 15]. NaPi-IIa is the predominant isoform, accounting for approximately 70-80% of renal phosphate reabsorption, while NaPi-IIc plays a smaller but significant role, particularly in humans [7, 43]. Their activity is tightly regulated by hormones such as parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), which promote their internalization and degradation to increase phosphate excretion [5, 16, 20]. Mutations in the genes encoding these transporters lead to various clinical syndromes, including idiopathic infantile hypercalcemia, hereditary hypophosphatemic rickets with hypercalciuria, and nephrolithiasis [2, 3, 12]. Pharmacological inhibition of NaPi-IIa and NaPi-IIc is being explored as a novel therapeutic strategy to manage hyperphosphatemia in patients with chronic kidney disease (CKD), where traditional phosphate binders are often insufficient [25, 38, 40]. Selective inhibitors like PF-06869206 and BAY-767 have shown promise in preclinical and early clinical studies by promoting phosphaturia and lowering serum phosphate levels [25, 36, 43].

Other names

SLC34A1SLC34A3NPT2aNPT2cNPTIIaNPTIIcSodium-phosphate cotransporter type IIa and IIcSolute carrier family 34 member 1Solute carrier family 34 member 3

Direct inhibition of sodium-dependent phosphate transport activity; reduction of transporter abundance on the apical membrane via endocytosis and lysosomal degradation; transcriptional suppression of transporter genes.