# Project-002

> **NIH NIH P20** · UNIVERSITY OF MISSISSIPPI MED CTR · 2022 · $268,835

## Abstract

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in young women, is characterized by 
hyperandrogenemia and metabolic dysfunction. PCOS women who become pregnant may have offspring born 
with low birth weight (LBW), associated with increased risk for cardiovascular (CV) disease (CVD) later in life. 
However, there are few studies on long-term consequences of PCOS pregnancy on the CV health in adult 
offspring, and most importantly, there is no information on sex differences in CVD in adult PCOS offspring. We 
use a well-characterized and clinically-relevant model of PCOS, the hyperandrogenemic female (HAF) rat. As in 
human PCOS offspring, both male and female offspring of HAF dams (F1HAF) are born with LBW. My preliminary 
data show that by 16 wks of age (adults), male F1HAF have decreased testosterone (T), increased intrarenal 
angiotensin (Ang) II and Ang converting enzyme (ACE), indicating activation of the intrarenal classical 
vasoconstrictor renin angiotensin system (RAS), an increase in inflammatory cytokines consistent with a 
senescence-associated secretory phenotype (SASP), proteinuria, and an enhanced pressor response to Ang II 
infusion. A senolytic cocktail (dasatinib and quercetin) in male F1HAF decreases proteinuria and BP. In contrast, 
my preliminary data show that female F1HAF have no change in T levels, no activation of the vasoconstrictor RAS 
(similar intrarenal ACE and Ang II, lower Ang II type 1 receptor (AT1R) expression) compared to controls, but 
they have increased ACE2 expression, suggesting activation of the intrarenal non-classical vasodilator RAS. In 
addition, female F1HAF are normotensive with no proteinuria, and they have an increase in anti-inflammatory 
renal regulatory T cells (Tregs) and a decrease in pro-inflammatory T helper 17 cells (TH17). Their BP is also 
refractory to infused Ang II, suggesting that female F1HAF are protected against programmed CV risk in adulthood. 
In the proposed studies I will test the following hypotheses: 1) Adult male F1HAF develop an activation of the 
intrarenal vasoconstrictor RAS that contributes to a decrease in renal Tregs, which promotes the 
development of inflammatory SASP causing renal injury and enhanced pressor response to Ang II; 2) 
Adult female F1HAF develop an activation of the intrarenal vasodilator RAS and upregulation of renal 
Tregs, thus protecting from renal injury and the pressor response to Ang II, in the following specific aims: 
Aim 1: To test the hypothesis that adult male F1HAF have an activation of the intrarenal vasoconstrictor RAS 
(increased renal cortical ACE, Ang II, and AT1R), that causes a decrease in renal Tregs which promotes the 
development of renal cortical inflammatory cytokines and SASP, leading to renal injury and reduction in renal 
function along with an enhanced pressor response to Ang II. Aim 2: To test the hypothesis that adult female 
F1HAF have an activation of the intrarenal vasodilator RAS (increased renal...

## Key facts

- **NIH application ID:** 10657010
- **Project number:** 2P20GM121334-06
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Noha Shawky
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $268,835
- **Award type:** 2
- **Project period:** 2017-06-08 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10657010

## Citation

> US National Institutes of Health, RePORTER application 10657010, Project-002 (2P20GM121334-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10657010. Licensed CC0.

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