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Principal Investigator: Noha Shawky
Organization: UNIVERSITY OF MISSISSIPPI MED CTR
Fiscal Year: 2022
Award: $268,835
Funding agency: National Institute of General Medical Sciences
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 cortical ACE2, AT2R and Mas R) and
an increase in renal Tregs, which in turn causes them to be protected from renal injury and refractory to the Ang
II pressor response.
Terms: <21+ years old><ACE2><Adult><Adult Children><Adult Daughters><Adult Human><Adult Offspring><Adult Sons><Age><AngII><Angiotensin AT1 Receptor><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Angiotensin II Type 1 Receptor><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><CD143 Antigens><Carboxycathepsin><Cell Body><Cells><Common Rat Strains><Dasatinib><Data><Development><Differences between sexes><Differs between sexes><Dipeptidyl Peptidase A><Disease><Disorder><Endocrine Diseases><Endocrine Diseases and Manifestations><Endocrine System Diseases><Enzyme Gene><Enzymes><Female><Gestation><Human><Hyperandrogenemia><Inflammatory><Infusion><Infusion procedures><Injury to Kidney><Kidney><Kidney Urinary System><Kininase A><Kininase II><Life><Low Birth Weight Infant><Metabolic dysfunction><Mississippi><Modeling><Modern Man><Peptidyl-Dipeptidase A><Perinatal><Peripartum><Phase><Phenotype><Polycystic Ovarian Disease><Polycystic Ovarian Syndrome><Polycystic Ovary Syndrome><Pregnancy><Proteinuria><Quercetin><Rat><Rats Mammals><Rattus><Receptor Protein><Receptor, Angiotensin, Type 1><Refractory><Regulatory T-Lymphocyte><Renal function><Renin-Angiotensin System><Research><Sclerocystic Ovarian Degeneration><Sclerocystic Ovary Syndrome><Sex Differences><Sexual differences><Testing><Testosterone><Therapeutic Testosterone><Trans-Testosterone><Treg><Up-Regulation><Upregulation><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasodilating Agent><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Vasopressor Agents><Woman><adolescent woman><adolescent women><adulthood><ages><angiotensin converting enzyme 2><angiotensin converting enzyme II><antiinflammatory><cardiovascular disease risk><cardiovascular disorder risk><cardiovascular health><cardiovascular risk><cardiovascular risk factor><clinical relevance><clinically relevant><cytokine><developmental><endocrine disorder><kidney function><kidney injury><low birth weight><low birth weight infant human><low birthweight><male><normotensive><offspring><polycystic ovary><polycystic ovary disease><polycystic ovary disorder><pregnant><receptor><receptor expression><regulatory T-cells><renal><renal injury><response><senescence><senescent><sex-dependent differences><sex-related differences><sex-specific differences><vasopressor><young woman>