**3.1.1 Sodium-hydrogen exchanger isoform 3**

Sodium-hydrogen exchanger isoform 3 (NHE3), the main NHE isoform of PTCs, mediates isotonic reabsorption of approximately two-thirds of filtered NaCl and water, the reabsorption of bicarbonate, and the secretion of ammonium (Bobulescu and Moe 2009). It also contributes to the reabsorption of filtered citrate, amino acids, and oligopeptides by providing H+ used by H+-coupled cotransporters. Indeed, enhanced NHE3 activity is assumed to be a factor for the increased sodium reabsorption and the development of hypertension in diabetes. NHE3 was reported to interact with megalin in PTC intermicrovillar clefts (Biemesderfer et al. 1999; Biemesderfer, DeGray, and Aronson 2001) and, following endocytosis with megalin, it is postulated to utilize the outward transvesicular sodium gradient of endocytic vesicles and early endosomes to drive the inward movement of H+ and endosomal acidification. This is important for dissociating reabsorbed ligand proteins from megalin both for further processing and megalin recycling to the cell surface. Hormonal regulation of NHE3 has been intensively investigated and reviewed elsewhere (Bobulescu and Moe 2009).
