*2.1. Proximal Tubule*

Among the salt transport mechanisms in the PT, NHE3 has a major role in sodium reabsorption in this segmen<sup>t</sup> [18,19]. Human NHE3 contains a PY motif that binds to ubiquitin ligase neuronal precursor cell-expressed developmentally downregulated 4-2 (NEDD4-2), and this interaction can modulate cell surface expression and internalization of NHE3 [20], although it is unclear whether NHE3 is directly ubiquitylated by Nedd4-2. It is interesting to note that this interaction appears to be exclusive to humans and several primates, which is because the PY motif in NHE3 was not identified in other mammals in the alignment analysis. Hatanaka et al. reported that angiotensin II signaling alters NHE3 levels, thereby regulating salt sensitivity [21]. Using subtotal nephrectomized mice, they showed that NHE3 abundance was lower in subtotal nephrectomized mice receiving azilsartan, an angiotensin II receptor 1 (AT1R) blocker, than in those receiving vehicle and that lactacystin, a proteasome inhibitor, blocked the azilsartan-induced decrease in NHE3 expression. These data indicate that NHE3 levels are regulated by UPS that are modulated by AT1R signaling. It currently remains unknown whether the interaction between NHE3 and NEDD4-2 is regulated by angiotensin II.
