Jennifer Sullivan’s research while affiliated with Augusta University and other places

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Publications (48)


Abstract P359: Greater NLRP3 in Males Results in a More Pro-Inflammatory T cell Profile, but Comparable Increases in Blood Pressure to Females with DOCA-Salt
  • Article

September 2024

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1 Read

Hypertension

Cameron Liss

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Kasey Belanger

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Jeanine Badrak

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[...]

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Jennifer Sullivan

T cells contribute to the development of hypertension, but what mediates T cell activation in hypertension is still being investigated. The NLRP3 inflammasome is a key mediator of the inflammatory response, and NLRP3 contributes to deoxycorticosterone acetate (DOCA)-salt hypertension in male mice. Little is known regarding the role of NLRP3 in hypertensive females, but we previously published that greater increases in blood pressure (BP) in male DOCA-salt rats vs females is associated with a more pro-inflammatory T cell profile. The goal of the current study was to test the hypothesis that greater NLRP3 activation in males contributes to greater increases in BP and a more pro-inflammatory T cell profile than in females. Methods: Initial studies measured NLRP3 and IL1-β mRNA expression in kidneys of uninephrectomized (UNX) male and female Sprague Dawley rats randomized to vehicle or DOCA treatment (n=5/group). Additional UNX male and female rats were randomized to DOCA plus vehicle or an NLRP3 inhibitor, MCC950 (10 mg/kg), for 3 weeks. BP was measured via telemetry (n=5/group). Kidneys were harvested for flow cytometric analysis of T cells. Data were compared via 2-way ANOVA. Results: DOCA increased renal NLRP3 and IL1-β mRNA in males and females (NLRP3: P treatment <0.0001, P sex =0.0014; IL1-β: P treatment <0.0001, P sex =0.05), and increases were greater in males (P interaction =0.04, P interaction =0.02, respectively). DOCA treatment increased BP in males (105±4 to 190±1 mmHg) and females (97±3 to 167±5 mmHg), and treatment with MCC950 attenuated DOCA-induced increases in BP in both sexes (males: 107±3 to 174±2 mmHg; females: 98±3 to 159±7 mmHg; P treatment =0.004). Terminal BP values were compared and while BP was higher in males, the impact of MCC950 was comparable between the sexes (P sex =0.0001; P interaction =0.4). However, MCC950 attenuated DOCA-induced increases in renal CD4 + T cells and Th17 cells to a greater degree in males than in females (CD4+: P treatment <0.001, P sex =0.03, P interaction =0.04; Th17 cells: P treatment <0.001, P sex =0.001, P interaction =0.04). Conclusions: NLRP3 contributes to the development of DOCA-salt induced increases in BP and inflammation in both males and females. However, males have greater NLRP3-mediated increases in renal T cells than females. The impact of this mechanism on renal function and the potential for targeted hypertensive therapies needs to be further examined.



Early-Onset Hypertension and Sex-Specific Residual Risk for Cardiovascular Disease in Type 2 Diabetes

April 2024

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6 Reads

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3 Citations

Diabetes Care

OBJECTIVE To investigate whether the sex disparities in type 2 diabetes–associated cardiovascular disease (CVD) risks may be related to early-onset hypertension that could benefit from intensive blood pressure (BP) control. RESEARCH DESIGN AND METHODS We analyzed intensive versus standard BP control in relation to incident CVD events in women and men with type 2 diabetes, based on their age of hypertension diagnosis. RESULTS Among 3,792 adults with type 2 diabetes (49% women), multivariable-adjusted CVD risk was increased per decade earlier age at hypertension diagnosis (hazard ratio 1.11 [1.03–1.21], P = 0.006). Excess risk associated with early-diagnosed hypertension was attenuated in the presence of intensive versus standard antihypertensive therapy in women (P = 0.036) but not men (P = 0.76). CONCLUSIONS Women with type 2 diabetes and early-onset hypertension may represent a higher-risk subpopulation that not only contributes to the female excess in diabetes-related CVD risk but may benefit from intensive BP control.


Editorial: Sex differences in renal physiology
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  • Full-text available

November 2023

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17 Reads

Download

Sustained mitochondrial dysfunction in male, but not female Spontaneous Hypertensive Rats (SHR) corresponds with delayed renal recovery from ischemic injury

May 2023

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1 Read

Physiology

Acute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication in hospital settings with high mortality rates. The mechanisms mediating renal IR injury and leading to increased risk of later developing cardiovascular and renal diseases in either sex remain poorly understood. We previously reported that there is sex difference in renal recovery from IR where males have a delayed recovery vs females. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of AKI in males, resulting in abnormal kidney repair and disease progression. However, the impact of IR on mitochondrial function in females has not been examined. The goal of the current study was to test the hypothesis that IR results in greater sustained mitochondrial dysfunction in males vs. females corresponds to delayed recovery of renal function in males. 13-week-old male and female SHR were subjected to sham or 30-minute warm bilateral IR. Subsets of rats were euthanized 1- or 7-days post-IR (n=6/group). Blood was collected to measure kidney function. The right kidney was dissected and processed for electron microscopy (EM) to assess mitochondrial structure, histological analysis of renal structure, and measurement of mitochondrial DNA (mtDNA) copy number via RT-PCR. Tubular cells were isolated from the left kidney to measure oxygen consumption rate (OCR) to assess mitochondrial respiration using Seahorse XFe24 Extracellular Flex Analyzer. IR increased plasma creatinine (Pcr) in male and female SHR vs. respective sham controls 1-day post-IR (PIR =0.0001; Psex✕IR=0.2). Pcr remained elevated in male, but not female, SHR 7 days post-IR (Pcr: PIR =0.03; Psex✕IR=0.04). OCR was reduced in male and female tubules 1 day post IR (PIR =0.001; Psex=0.94) and remained reduced only in tubules from males 7 days post-IR (PIR =0.0001; Psex✕IR=0.0001). Consistent with decreased OCR, EM revealed swollen round mitochondria, reduced mitochondria density with complete loss of cristae membranes vs. sham controls 1-day post-IR in both sexes, which was sustained 7 days post-IR only in males. Mitochondrial DNA copy number and peroxisome proliferator-activator receptor-y coactivator (PGC-1α) mRNA expression was also reduced 1-day post-IR in both sexes (PIR =0.05; Psex✕IR=0.59) and remained down only in males 7 days post-IR (PIR =0.02; Psex✕IR=0.001). In conclusion, our data demonstrate that there is sex difference in mitochondria after renal IR. Males have sustained mitochondrial dysfunction with delayed renal recovery compared to females. Further studies will be carried out to better understand the direct impact of mitochondria dysfunction on renal recovery post-IR in male and females. This work was supported by career development grant from AHA (20CDA35310362) to R Mohamed; National Institutes of Health (1P01HL134604-01 and R01 HL127091 to J. C. Sullivan. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.


Zinc finger protein 24-dependent transcription factor SOX9 up-regulation protects tubular epithelial cells during acute kidney injury

March 2023

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46 Reads

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14 Citations

Kidney International

Transcriptional profiling studies have identified several protective genes upregulated in tubular epithelial cells during acute kidney injury (AKI). Identifying upstream transcriptional regulators could lead to the development of therapeutic strategies augmenting the repair processes. SOX9 is a transcription factor controlling cell-fate during embryonic development and adult tissue homeostasis in multiple organs including the kidneys. SOX9 expression is low in adult kidneys, however, stress conditions can trigger its transcriptional upregulation in tubular epithelial cells. SOX9 plays a protective role during the early phase of AKI and facilitates repair during the recovery phase. To identify the upstream transcriptional regulators that drive SOX9 upregulation in tubular epithelial cells, we used an unbiased transcription factor screening approach. Preliminary screening and validation studies show that zinc finger protein 24 (ZFP24) governs SOX9 upregulation in tubular epithelial cells. ZFP24, a Cys2-His2 (C2H2) zinc finger protein is essential for oligodendrocyte maturation and myelination, however, its role in the kidneys or in SOX9 regulation remains unknown. Here, we found that tubular epithelial ZFP24 gene ablation exacerbated ischemia, rhabdomyolysis, and cisplatin-associated AKI. Importantly, ZFP24 gene deletion resulted in suppression of SOX9 upregulation in injured tubular epithelial cells. Chromatin immunoprecipitation and promoter luciferase assays confirmed that ZFP24 bound to a specific site in both murine and human SOX9 promoters. Importantly, CRISPR/Cas9 mediated mutation in the ZFP24 binding site in the SOX9 promoter in vivo led to suppression of SOX9 upregulation during AKI. Thus, our findings identify ZFP24 as a critical stress-responsive transcription factor protecting tubular epithelial cells through SOX9 upregulation.



FIGURE 1 | Aging mechanisms. This figure represents the aging mechanisms and the interrelationship between the several intrinsic factors that affect this process.
FIGURE 2 | Sex differences in aging mechanisms. This figure shows evidence linking sex-differences to aging-mechanisms.
Sex Differences in Molecular Mechanisms of Cardiovascular Aging

September 2021

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131 Reads

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28 Citations

Frontiers in Aging

Cardiovascular disease (CVD) is still the leading cause of illness and death in the Western world. Cardiovascular aging is a progressive modification occurring in cardiac and vascular morphology and physiology where increased endothelial dysfunction and arterial stiffness are observed, generally accompanied by increased systolic blood pressure and augmented pulse pressure. The effects of biological sex on cardiovascular pathophysiology have long been known. The incidence of hypertension is higher in men, and it increases in postmenopausal women. Premenopausal women are protected from CVD compared with age-matched men and this protective effect is lost with menopause, suggesting that sex-hormones influence blood pressure regulation. In parallel, the heart progressively remodels over the course of life and the pattern of cardiac remodeling also differs between the sexes. Lower autonomic tone, reduced baroreceptor response, and greater vascular function are observed in premenopausal women than men of similar age. However, postmenopausal women have stiffer arteries than their male counterparts. The biological mechanisms responsible for sex-related differences observed in cardiovascular aging are being unraveled over the last several decades. This review focuses on molecular mechanisms underlying the sex-differences of CVD in aging.


Stimulation of angiotensin II receptor 2 preserves cognitive function and is associated with an enhanced cerebral vascular density after stroke

September 2021

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69 Reads

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8 Citations

Vascular Pharmacology

Angiotensin signaling is known to be sexually dimorphic. Although it is a well-studied target for intervention in stroke and cognitive impairment, female studies are rare. With females suffering a disproportionately greater negative impact of stroke and dementia vs. males, effective interventions are of utmost urgency. The aim of the current study was to determine the impact of activation of the angiotensin II type 2 receptor (AT2R) with the agonist compound 21 (C21) on the development of post-stroke cognitive impairment, after experimental ischemic stroke. Ovariectomized (OVX) spontaneously hypertensive rats (SHRs) were subjected to 1 h of middle cerebral artery occlusion (MCAO). At 24 h, rats with a significant neurologic deficit were randomized to receive either saline or C21 (0.03 mg/kg/day) intraperitoneally (IP) for 5 days, then orally (0.12 mg/kg/day) for a total of 6 weeks. Cognitive function, brain structure by MRI and vascular architecture by microCT angiography were measured. C21 preserved cognitive function, specifically spatial memory, and improved vascular density in the ischemic hemisphere at 6 weeks, reflecting both arteriogenesis and angiogenesis. In conclusion, C21 prevented cognitive impairment after stroke, likely through a mechanism involving vascular protection and restoration.


Known mechanisms mediating sex difference in BP in SHR and supporting literatures
Sex differences in hypertension: Lessons from spontaneously hypertensive rats (SHR)

August 2021

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312 Reads

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41 Citations

Clinical Science

Although numerous clinical and experimental studies have clearly identified a sexual dimorphism in blood pressure control, the mechanism(s) underlying gender differences in blood pressure remain unclear. Over the past two decades, numerous laboratories have utilized the spontaneously hypertensive rats (SHR) as an experimental model of essential hypertension to increase our understanding of the mechanisms regulating blood pressure in males and females. Previous work by our group and others have implicated that differential regulation of adrenergic receptors, the renin–angiotensin system, oxidative stress, nitric oxide bioavailability and immune cells contribute to sex differences in blood pressure control in SHR. The purpose of this review is to summarize previous findings to date regarding the mechanisms of blood pressure control in male versus female SHR.


Citations (17)


... Recent analysis of data by Yang et al. demonstrated that individuals diagnosed with both hypertension and diabetes face a higher risk of cardiovascular disease events compared to those with hypertension alone (18). The cardiomyopathy associated with T2DM and hypertension is characterized by pathological changes in the left ventricular myocardium, initially manifesting as diastolic dysfunction with preserved systolic function (4,28,29). With disease progression, there is a risk of developing left ventricular systolic dysfunction, which can lead to heart failure with reduced ejection fraction and, in severe cases, mortality (30). ...

Reference:

The impact of type 2 diabetes on left ventricular function in hypertensive patients: a three-dimensional speckle-tracking imaging study
Early-Onset Hypertension and Sex-Specific Residual Risk for Cardiovascular Disease in Type 2 Diabetes
  • Citing Article
  • April 2024

Diabetes Care

... We have recently reported that oral NaHCO 3 ingestion promotes inflammatory (M1) to antiinflammatory (M2) macrophage polarization in the spleen and kidney of Dahl SS rats, and that changes in macrophage polarization are dependent on the presence of the spleen [22]. Flow cytometry data from whole spleen of both wild-type and Hv1 −/− mutant Dahl SS rats treated with either vehicle or NaHCO 3 after 2 weeks of HS are presented in Figure 6. ...

Bicarbonate therapy has no effect on renal T‐cell infiltration or blood pressure but markedly reduces tubular casts/fibrosis and is associated with an M1 to M2 polarization in Dahl salt‐sensitive rats
  • Citing Article
  • April 2016

The FASEB Journal

... In addition, genes that typically mark stem cells and are involved in repair, such as PROM1 (CD133) and SOX 9, are upregulated post injury [17][18][19] . However, persistent activation of these genes is frequently associated with maladaptive repair and progressive fibrosis 1,18,20 . ...

Zinc finger protein 24-dependent transcription factor SOX9 up-regulation protects tubular epithelial cells during acute kidney injury
  • Citing Article
  • March 2023

Kidney International

... Various co-morbid conditions that present with CKD are: hypertension, diabetes, HIV/AIDS, cardiovascular diseases etc (11,14,15). However, the co-morbid condition of CKD and hypertension is considered the leading cause of death globally (16,17). ...

Editorial: Hypertension and Chronic Kidney Injury or Failure, Volume II

... Additionally, the effects of NF-κB suppression on other cardiac cell types, such as endothelial cells, fibroblasts, and smooth muscle cells, should be investigated to better understand the broader impact of NF-κB signaling in cardiac aging. It is also crucial to include female mice in future studies to assess potential sex-related differences in NF-κB signaling and its role in heart aging, as suggested by previous studies [52,53]. ...

Sex Differences in Molecular Mechanisms of Cardiovascular Aging

Frontiers in Aging

... The brain renin-angiotensin system (RAS) is involved in the pathogenesis of stroke [22][23][24][25][26][27][28][29][30][31][32][33][34]. We and others have demonstrated that C21, the first selective non-peptide AT2R agonist, provides a neurovascular protective effect and enhances sustained functional improvement after stroke [23,31,[33][34][35][36][37][38][39][40][41][42][43][44]. Direct stimulation of AT2R via C21 has been shown to improve functional recovery after stroke without affecting blood pressure in hypertensive animals, even at higher doses [38,45]. ...

Stimulation of angiotensin II receptor 2 preserves cognitive function and is associated with an enhanced cerebral vascular density after stroke
  • Citing Article
  • September 2021

Vascular Pharmacology

... Juvenile males have a higher prevalence of hypertension as compared to premenopausal females, but this difference disappears following menopause [42]. However, women are at a greater risk for developing hypertension-related cardiovascular disease [43].There are numerous reports of sex differences in angiotensin signaling and blood pressure [44][45][46][47], the inflammatory profile [48][49][50][51][52], noradrenergic content and turnover rate [52,53], differential regulation of adrenergic receptors [54], and sympathetic activity [55] of male and female SHR. Our results support a potential mechanistic role for Ephx2 and Esr1 to explain the differential regulation of female-specific multi-organ effects. ...

Sex differences in hypertension: Lessons from spontaneously hypertensive rats (SHR)

Clinical Science

... Bouhaddou et al. [42] developed a semi-mechanistic PK/PD mathematical model for an anticancer drug ORY-1001 (epigenetic inhibitor) using the in vitro cell culture data sets. They predicted the in vivo tumor growth dynamics To predict the effects of an individual's sex and individual pathophysiology on treatment response for different classes of antihypertensive drugs in rat models Ahmed et al. [43] developed the first sex-specific QSP model of primary hypertension in rats based on previously published models of blood pressure regulation. They integrated it with a machine learning model and predicted that women respond better than men to ACEi, ARB/TZD dual therapy, and CCB Translational (preclinical to clinical) ...

Impact of sex and pathophysiology on optimal drug choice in hypertensive rats: Quantitative insights for precision medicine

iScience

... It is reported that the disease appears more with increasing age, but all age groups are at risk of being affected by kidney diseases, and most of these patients have hypertension which can damage blood vessels and the kidney's filtering apparatus [5][6][7][8]. ...

Editorial: Hypertension and Chronic Kidney Injury or Failure

... As observed in several preclinical studies, in females, dendritic cells migrating from the periphery into the ischemic brain area exhibit higher levels of TLRs [124], resulting in a better antigen presentation compared to males. The different expression of TLRs between the two sexes is linked to the presence of many TLR genes (e.g., TLR2, TLR3, and TLR7) on the X chromosome [125]. ...

Toll-Like Receptors Contribute to Sex Differences in Blood Pressure Regulation

Journal of Cardiovascular Pharmacology