Fig. 7.

Scheme showing that extracellular (endocrine and paracrine) angiotensin (Ang) II is taken up via Ang II type 1a receptor (AT_1aR)-mediated internalization and then results in G_q/11/phospholipase C (PLC) signaling. Under physiologic conditions (low Ang II), internalized Ang II is sorted to the lysosomal pathway for degradation, whereas AT_1a receptors recycle back to the membrane. Alternatively, particular at sustained high extracellular Ang II levels, the Ang II–AT_1aR complex may bypass the lysosomal degradation pathway, allowing its transport to mitochondria and nucleus, where Ang II activates AT_1aR and/or Ang II type 2 receptor (AT₂R) to alter mitochondrial oxidative and glycolysis stress responses. This may in turn alter the expression or activity of Na⁺/H⁺ exchanger 3 (NHE3) on the apical membranes, or Na⁺/K⁺-ATPase and the Na⁺/HCO₃⁻ cotransporter on the basolateral membranes in the proximal tubules. Thus, activation of the mitochondrial Ang II/AT_1aR/O₂⁻ signaling will stimulate proximal tubule sodium reabsorption, impair the pressure-natriuresis response, and elevate blood pressure. Conversely, activation of the mitochondrial Ang II/AT₂R/NO/cGMP signaling by overexpressing AT₂R in the mitochondria will likely inhibit proximal tubule sodium reabsorption, augment the pressure-natriuresis response, and lower blood pressure. Modified from Li et al. (2020, 2021).