The present study tested the hypotheses that overexpression of an intracellular Ang II (angiotensin II) fusion protein, mito-ECFP/Ang II, selectively in the mitochondria of mouse proximal tubule cells induces mitochondrial oxidative and glycolytic responses and elevates blood pressure via the Ang II/AT
1a
receptor/superoxide/NHE3 (the Na
+
/H
+
exchanger 3)-dependent mechanisms. A PT-selective, mitochondria-targeting adenoviral construct encoding Ad-sglt2-mito-ECFP/Ang II was used to test the hypotheses. The expression of mito-ECFP/Ang II was colocalized primarily with Mito-Tracker Red FM in mouse PT cells or with TMRM in kidney PTs. Mito-ECFP/Ang II markedly increased oxygen consumption rate as an index of mitochondrial oxidative response (69.5%;
P
<0.01) and extracellular acidification rate as an index of mitochondrial glycolytic response (34%;
P
<0.01). The mito-ECFP/Ang II–induced oxygen consumption rate and extracellular acidification rate responses were blocked by AT
1
blocker losartan (
P
<0.01) and a mitochondria-targeting superoxide scavenger mito-TEMPO (
P
<0.01). By contrast, the nonselective NO inhibitor L-NAME alone increased, whereas the mitochondria-targeting expression of AT
2
receptors (mito-AT
2
/GFP) attenuated the effects of mito-ECFP/Ang II (
P
<0.01). In the kidney, overexpression of mito-ECFP/Ang II in the mitochondria of the PTs increased systolic blood pressure 12±3 mm Hg (
P
<0.01), and the response was attenuated in PT-specific PT-
Agtr1a
−/−
and PT-
Nhe3
−/−
mice (
P
<0.01). Conversely, overexpression of AT
2
receptors selectively in the mitochondria of the PTs induced natriuretic responses in PT-
Agtr1a
−/−
and PT-
Nhe3
−/−
mice (
P
<0.01). Taken together, these results provide new evidence for a physiological role of PT mitochondrial Ang II/AT
1a
/superoxide/NHE3 and Ang II/AT
2
/NO/NHE3 signaling pathways in maintaining blood pressure homeostasis.
Prevention of Both Direct and Cross-Priming of Antitumor CD8+ T-Cell Responses following Overproduction of Prostaglandin E2 by Tumor Cells In vivo
