# Novel Roles of Mitochondrial Angiotensin II in The Proximal Tubule of The Kidney

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2021 · $501,372

## Abstract

In the United States, one in three adults will develop hypertension and require antihypertensive treatments in
their lifetime. Yet only 1/2 of hypertensive patients respond to current antihypertensive drugs, and 1/3 of
hypertensive patients will continue to develop cardiovascular and renal complications. The mechanisms
underlying poorly controlled hypertension in response to current antihypertensive therapies remain
incompletely understood. Supported by NIDDK grants, we have established that: 1) circulating and tissue ANG
II is taken up by the proximal tubule (PT) via AT1a receptor-, the endocytic receptor megalin-, or caveolin 1-
dependent mechanisms; 2) internalized ANG II and AT1 (AT1a) receptors are localized in the endosomes and
nuclei of PT cells; 3) intracellular microinjection of ANG II increases [Ca ]i, whereas exposure of freshly
2+
isolated renal cortical nuclei with ANG II induces transcriptional TGF-β1, MCP-1, and the Na+/H+ exchanger 3
(NHE3) responses via AT1a receptors; 4) in vitro or intrarenal adenovirus-mediated overexpression of an
intracellular ANG II fusion protein with AT1a receptors selectively in the PT induces NHE3 expression, promotes
Na+ reabsorption, and increases blood pressure, and 5) global- or kidney-selective deletion of NHE3 attenuates
ANG II-induced hypertension. These studies strongly suggest that intracellular ANG II may play an important
role in the regulation of Na+ transport in the PT and blood pressure homeostasis. In this A1 revised proposal,
we will test a new hypothesis that in the PT of the kidney, ANG II and AT1 (AT1a) are internalized into the
mitochondria, where mito-ANG II exerts dual roles on the mitochondrial function via activation of the
AT1a/Ca2+/NADPH oxidase/O2.- and the AT2/eNOS/NO/cGMP signaling pathways. Activation of the AT1a/
Ca2+/NADPH oxidase/O2.- pathway induces mitochondrial respiratory and glycolysis stress, impairs
pressure natriuresis response, and increases blood pressure, whereas activation of the mitochondrial
AT2/eNOS/NO/cGMP pathway by ANG II promotes pressure natriuresis and lowers blood pressure. In
Aim 1, we will use high resolution electron microscopic autoradiography and intravital multiphoton imaging to
determine whether AT1 (AT1a) and AT2 receptors are localized in the mitochondria of the PT, and whether [125I]-
ANG II or Alexa 488®-ANG II is internalized into the mitochondria of the PT in mice. In Aim II, we will determine
whether overexpression of a mitochondria-targeting mito-ANG II in PT cells impairs mitochondrial function by
activating the AT1a/Ca2+/NADPH oxidase/O2.- signaling pathways, whereas overexpression of mito-AT2R
protects mitochondrial function by activating the AT2/eNOS/NO/cGMP signaling. The PT-specific sglt2 promoter
and the mitochondria-targeting sequence will be used to drive the overexpression of mito-ANG II, mito-AT1aR or
mito-AT2R in PT cells. In Aim III, we will determine whether activation of mito-AT1aR by mito-ANG II in the PT
induces mitoc...

## Key facts

- **NIH application ID:** 10251271
- **Project number:** 5R01DK067299-15
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Jia Long Zhuo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $501,372
- **Award type:** 5
- **Project period:** 2020-03-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10251271

## Citation

> US National Institutes of Health, RePORTER application 10251271, Novel Roles of Mitochondrial Angiotensin II in The Proximal Tubule of The Kidney (5R01DK067299-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10251271. Licensed CC0.

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