Angiotensin II (Ang II) has long been implicated in mediating mitochondrial dysfunction in cardiovascular, hypertension, and kidney diseases. However, whether it is circulating and paracrine Ang II or intracellular mitochondrial Ang II that induces mitochondrial dysfunction has not been studied previously. The present study tested the hypotheses that overexpression of an intracellular angiotensin II (Ang II) fusion protein, mito-ECFP/Ang II, selectively in the mitochondria of mouse proximal tubule (mPCT) 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 proximal tubule-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 mPCT cells or with TMRM in kidney proximal tubules. mito-ECFP/Ang II markedly increased oxygen consumption rate (OCR) as an index of mitochondrial oxidative response (69.5%;
P
<0.01) and extracellular acidification rate (ECAR) as an index of mitochondrial glycolytic response (34%;
P
<0.01). The mito-ECFP/Ang II-induced OCR and ECAR 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 non-selective 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 proximal tubules increased systolic blood pressure 12 ± 3 mmHg (
P
<0.01), and the response was attenuated in proximal tubule (PT)-specific PT-
Agtr1a
-/-
and PT-
Nhe3
-/-
mice (
P
<0.01). Conversely, overexpression of AT
2
receptors selectively in the mitochondria of the proximal tubules 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 proximal tubule mitochondrial Ang II/AT
1a
/superoxide/NHE3 and Ang II/AT
2
/NO/NHE3 signaling pathways in maintaining blood pressure homeostasis.
88 Lowe syndrome – old and new evidence of secondary mitochondrial dysfunction