Figure 6.

The schematic representation for novel biological and physiological roles of intracellular Ang II system in the mitochondria of the proximal tubules in the regulation of proximal tubule Na⁺ reabsorption and blood pressure homeostasis. In addition to local onsite formation, extracellular (endocrine and paracrine) Ang II is taken up by the proximal tubule cells via the AT₁ (AT_1a) receptor-mediated mechanism. Some internalized Ang II/AT₁ receptor complexes may bypass the lysosomal degradation pathway and be transported to other intracellular organelles, including the mitochondria and the nucleus, where Ang II activates AT₁ and/or AT₂ receptors in the mitochondria to alter mitochondrial oxidative and glycolysis stress responses. This may in turn alter the expression or activity of NHE3 on the apical membranes or Na⁺/K⁺-ATPase on the basolateral membranes in the proximal tubules. Thus, activation of the mito-Ang II/AT₁/O₂⁻ signaling will stimulate proximal tubule Na⁺ reabsorption and elevate blood pressure. Conversely, activation of the mito-Ang II/AT₂/NO/cGMP signaling by overexpressing AT₂ receptors selectively in the mitochondria will likely inhibit proximal tubule Na⁺ reabsorption, induce natriuretic response, and lower blood pressure.