# Protective Arm of the Renin Angiotensin System in Obese Kidney

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2020 · $403,516

## Abstract

Project Summary
Obesity is a risk factor for chronic as well as acute kidney injury (AKI). Chronic kidney injury arises as a result
of progressive loss of kidney function leading to irreversible damage, while AKI occurs as an abrupt loss of
kidney function and usually is reversible. In both processes, inflammation plays an important role in the
initiation and maintenance of the injury. Renal inflammation is influenced by an interplay of pro- and anti-
inflammatory cytokines released by kidney cells and macrophages (broadly defined M1 and M2 types). While
M1 type are pro-inflammatory and cause renal injury (chronic and acute), M2 are anti-inflammatory and help
repair post AKI during the recovery phase. Thus altering the interplay between kidney cells and macrophages
offers a potential novel target to combat local inflammation and protect the kidney from chronic as well acute
injury. Recently, we and others have revealed that angiotensin type 2 receptors (AT2R) exert anti-inflammatory
and reno-protective actions, novel functions of AT2R in addition to natriuresis and blood pressure regulation.
Our preliminary studies in pre-hypertensive obese rat and mice suggest that AT2R agonist treatment reduces
inflammatory cytokines and protects against chronic kidney injury as well as AKI. A series of in vitro
experiments in human kidney proximal tubule epithelial cells (HK-2) and macrophages (THP-1 cells) revealed
that AT2R activation increases IL-10, which may be critical pathway in reducing pro-inflammatory cytokines and
creating a cross-talk between proximal tubules and macrophages, including shifting macrophages from M1 to
M2 type. These studies provide a strong premise to hypothesize that AT2R activation promotes a cross-talk
(interplay) between kidney epithelial cells and macrophages, via the anti-inflammatory IL-10 pathway,
preventing chronic and acute kidney injury in obesity. Moreover, AT2R shifts the macrophage balance between
M1 and M2 types limiting kidney injury and promoting repair, particularly in AKI in obesity. To test this
hypothesis, Aim 1 is directed to determine that renal AT2R via IL-10 pathway reduces local inflammation and
protects kidney against chronic injury in obesity. Aim 2 will study that AT2R activation attenuates AKI and
promotes kidney repair via a macrophage polarity shift towards M2 type. Uninephrectomized obese Zucker rats
will be used and placed on normal saline for chronic kidney injury and subjected to ischemia/reperfusion (I/R)
for AKI. Kidney specific knockdown of AT2R and IL-10 will achieved by utilizing shRNA plasmid DNA
encapsulated in microbubble technology, to study the role of kidney AT2R and IL-10 in reno-protection, anti-
inflammation and kidney repair. To define AT2R gender bias, experiments to study the role of estrogen in
AT2R-mediated reno-protection in females have been included. State-of-the-art techniques will be employed to
determine biochemical, histological and molecular outcomes of kidney injury and...

## Key facts

- **NIH application ID:** 9899744
- **Project number:** 5R01DK117495-03
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** TAHIR HUSSAIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,516
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899744

## Citation

> US National Institutes of Health, RePORTER application 9899744, Protective Arm of the Renin Angiotensin System in Obese Kidney (5R01DK117495-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899744. Licensed CC0.

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