Pediatrics & Women's Health
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/32089
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Browsing Pediatrics & Women's Health by Author "Cunningham, Mark"
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Item Changes in Blood Pressure and Abundance of Kidney Sodium Channels in Postpartum Preeclamptic Rats(2023) McCafferty, Adair; Smith, Jonna; Smith, Savanna; Jones, Kylie; Castillo, Angie; Wiemann, Natalia; Owen, Malissa; Srivastava, Riti; Cunningham, MarkPurpose: Postpartum (PP) preeclamptic (PE) women have an increased risk of developing hypertension (HTN) and chronic kidney disease. However, the mechanisms of these diseases in PP PE women are not fully understood. Results from our previous studies show 10-week PP PE rats have HTN (PMID: 34727994). One factor that could cause elevated blood pressure is an increase in sodium transport in the kidneys of PP PE rats. Our current study will examine the BP as well as the amount of Sodium Potassium Chloride Cotransporters (NKCC), Sodium Hydrogen Exchanger-1 (NHE1) and a-subunit of the Epithelial Sodium Channel (ENaC) within the kidney of PE rats 6 weeks postpartum (PP6). We hypothesize that PP6 PE rats will have an increase in BP as well as increased amounts of NKCC, NHE1 and a-ENaC proteins. Methods: Pregnant Sprague Dawley rats were divided into 2 group: control (CON) normal pregnant rats and PE rats (derived from the surgically induced placental ischemic model of PE). All rats gave birth and were weaned for 3 weeks. At PP6, BP was measured via carotid catheterization. Kidney cortex (KC) and medulla (KM) tissue were collected to measure for NKCC, NHE1 and a-ENaC amounts via Western Blots. Results: BP was significantly elevated in PP6 vs CON rats (128 ± 6 vs 106 ± 4mmHg, p<0.05). The amount of NKCC channels within the KC was significantly increased in PP6 vs CON rats (107.82 ± 5.64 vs 100 ± 1.48 IU/Protein/CON%, p<0.05). The amount of a-ENaC proteins within the KC was also increased in PP6 vs CON rats (123.4 ± 4.67 vs 116.5 ± 33.03 IU/Protein/CON%, p=0.06). NHE1 channels within the KC were slightly decreased in PP6 vs CON rats (77.31 ± 15.28 vs 100 ± 16.61 IU/Protein/CON%, N.s). No changes were observed in a-ENaC proteins within the KM in PP6 vs CON rats. Conclusion: PP6 PE rats have HTN as well as increased NKCC and a-ENaC sodium transport proteins in the kidney cortex. These results confirm our hypothesis that increased sodium transporters in the kidney, which could elevate sodium and water reabsorption, correlates with an increase in blood pressure. This study is clinically relevant because it informs clinicians on the pathophysiology of HTN and renal disease/dysfunction in PP PE women. It also highlights novel approaches to providing potential therapies to manage blood pressure in PP PE women. Future studies will investigate the cause-and-effect relationship between blood pressure and sodium handling in the kidney of PP PE rats.Item Changes in cardiac oxidative stress, nitric oxide bioavailability, mitochondrial function, and blood pressure in postpartum preeclamptic rats(2023) Owen, Malissa; Smith, Jonna; Smith, Savanna; Jones, Kylie; Castillo, Angie; Wiemann, Natalia; McCafferty, Adair; Srivastava, Prakriti; Cunningham, MarkBackground: Preeclampsia (PE) is characterized by new onset hypertension (HTN) during pregnancy that usually occurs in the third trimester and is associated with decreased nitric oxide (NO) bioavailability, increased oxidative stress (OS), and mitochondrial dysfunction. Postpartum (PP) PE women have an increased risk of developing HTN and cardiovascular diseases (CVD) later in life. The timing and mechanisms of this rise in blood pressure (BP) and cardiovascular dysfunction in PP PE women are unknown. Previous studies in our lab indicate that PP PE rats have HTN, increased OS, and cardiac mitochondrial dysfunction at 10 weeks (PP10) (PMID: 34727994). Our current study examines the relationship between BP and cardiac NO bioavailability, OS, and mitochondrial dysfunction at 6 weeks (PP6), an earlier time point from our previous study. We hypothesize that PP6 PE rats will have HTN, increased cardiac OS, decreased cardiac NO bioavailability, and mitochondrial dysfunction. Methods: Pregnant Sprague Dawley rats were divided into 2 groups: normal pregnant rats (NP) and PE rats, derived from the surgically induced reduced uterine perfusion pressure model of PE (RUPP). All rats gave birth, and their offspring were weaned for 3 weeks. At PP6, BP was measured via carotid catheterization and heart tissues were collected to measure heat shock protein (HSP-1) (a measure of OS), copper zinc superoxide dismutase (CuZnSOD) (an antioxidant), manganese SOD (MnSOD) (a mitochondrial specific antioxidant), endothelial NOS (eNOS) (a measure of NO producing enzyme), and electron transport chain (ETC) proteins (a measure of mitochondrial function). These quantities were obtained through Western blots. Results: BP was significantly elevated in PP RUPP vs PP NP rats (128±6 vs 106±4mmHg, p < 0.05). HSP-1 was significantly decreased in PP RUPP vs PP NP rats (88±1.51 vs 100±4.05IU/Protein/CON%, p < 0.05). CuZnSOD showed no change between the two groups while MnSOD was drastically increased in PP RUPP vs PP NP (123±2.91 vs 100±5.30IU/Protein/CON%, p < 0.05). eNOS and ETC proteins were unchanged between PP RUPP and PP NP rats. Conclusion: Contrary to our hypothesis, PP6 PE rats have HTN with no increase in cardiac OS (due to decreased HSP-1 and increased in MnSOD amount) or decrease in cardiac NO bioavailability and mitochondrial dysfunction. These observations are different from our 10-week PP PE rats and may suggest that the heart is protected at 6 weeks PP despite the increase in blood pressure. Future studies will focus on the time frame in which cardiac dysfunction occurs in PP PE rats. Additionally, studies will explore the antioxidant, NO, and mitochondrial pathways along with other cellular mechanisms that may prevent the heart from damage and/or dysfunction after a PE pregnancy. This study is clinically relevant because it will inform clinicians on the mechanisms of HTN and cardiac dysfunction in women following a PE pregnancy as well as provide insights on therapies that could be used to prevent the development of CVDs later in life for PP PE women.Item Changes in cerebral inflammation and blood pressure in postpartum preeclamptic rats(2023) Wiemann, Natalia; Smith, Jonna; Smith, Savanna; Jones, Kylie; Castillo, Angie; Cromartie, Whitney; Owen, Malissa; McCafferty, Adair; Srivastava, Prakriti; Cunningham, MarkIntroduction: Postpartum (PP) preeclamptic (PE) women have an increased risk of developing hypertension (HTN) and cerebrovascular diseases later in life. Studies show that women who experience preeclampsia go on to develop HTN 7-8 years earlier than women with normal pregnancies, increasing their risk for developing cerebrovascular diseases such as stroke. While the timing and mechanisms contributing to a rise in blood pressure (BP) and cerebrovascular dysfunction in postpartum preeclamptic women are unknown, they are hypothesized to be influenced by inflammation. Previous studies in our lab indicate postpartum PE rats at 10 weeks have HTN and increased inflammation (PMID: 34727994). Our current study will examine BP and inflammation in postpartum PE rats at an earlier time point, 6 weeks (PP6), to determine the relationship between cerebral inflammation and the pathophysiology of HTN. We hypothesize that postpartum PE rats will have an increase in BP and cerebral inflammation 6 weeks after delivery. Methods: Pregnant Sprague Dawley rats were divided into 2 groups: normal pregnant (NP) rats, and preeclamptic (RUPP) rats. Placental ischemia was surgically induced in the preeclamptic group via the reduced uterine perfusion pressure (RUPP) model. All rats gave birth naturally and were weaned for 3 weeks. At PP6, BP was measured via carotid catheterization, and brain tissue was collected to measure pro-inflammatory (TNF-α and IL-17) and anti-inflammatory (IL-4 and IL-10) factors via colorimetric assays and ELISAs. Results: Blood pressure was elevated in RUPP PP vs NP PP (128±6 vs 106±4mmHg, p<0.05). Cerebral TNF-α drastically increased by ~2.4 fold in RUPP PP vs NP PP (2576±445.6 vs 1058±212.5pg/mL, ns). Cerebral IL-17(331.2±41.1 vs 297.6±48.6pg/mL, ns) and IL-4 (178.4±23.4 vs 154.8±14pg/mL, ns) also increased in RUPP PP vs NP PP. Cerebral IL-10 (103.9±21.4 vs 147.6±11.3pg/mL, ns) was decreased in RUPP PP vs NP PP rats. Conclusion: PP6 preeclamptic rats have HTN and increased cerebral inflammation. It is yet to be determined whether cerebral inflammatory markers are the cause or consequence of HTN in PP6 PE rats. Future studies will explore the sequence of HTN and cerebral inflammation in postpartum PE rats and determine how brain inflammation contributes to HTN and cerebral damage. We will also target specific areas of the brain that modulate autonomic function and BP. This study is clinically relevant because it will inform providers on the pathophysiology of HTN and/or cerebral damage in women after a PE pregnancy. Our findings suggest that the use of inflammatory therapeutic targets improves HTN and cerebrovascular dysfunction in postpartum PE women.Item A new rodent model of preeclampsia: Pregnant daughters from hypertensive placental ischemic moms have hypertension(2023) Smith, Jonna; Powell, Madison; Cromartie, Whitney; Smith, Savanna; Jones, Kylie; Castillo, Angie; Wiemann, Natalia; McCafferty, Adair; Owen, Malissa; Srivastava, Prakriti; Cunningham, MarkPurpose: Studies show that daughters from hypertensive pregnancies are twice as likely to have preeclampsia (PE), pregnancy-induced hypertension (HTN) in comparison to women born from a normal pregnancy. PE affects ~5-10% of all births in the USA and is the leading cause of intrauterine growth restriction (IUGR). PE is associated with oxidative stress (OS) and cerebral damage. The causes of PE are unknown but is influenced by genetic and environmental conditions. Studies show that pregnancies involving placental insufficiency and HTN create an adverse environment that can affect the IUGR baby’s developmental programming and pregnancy outcomes. This study aims to characterize the pregnancy of IUGR rat offspring from hypertensive placental ischemic moms. We hypothesize female rats born from pregnant hypertensive placental ischemic moms will have elevated blood pressure (BP) and OS. Methods: Pregnant Sprague Dawley moms are divided into 2 groups: normal pregnant (NP) and the reduced uterine perfusion pressure (RUPP) hypertensive placental ischemic rats. On day 14 of pregnancy, the RUPP surgery is performed to generate PE. All dams (NP and RUPP) give birth naturally and weaned for 3 weeks. Offspring were then separated by sex and mother’s pregnancy status. ~10 weeks later, offspring were mated according to 4 groups: ♀NP x ♂NP (CON Preg, n=3), ♀NP x ♂RUPP (n=2), ♀RUPP x ♂NP (IUGR Preg, n=5), ♀RUPP x ♂RUPP (n=4). On day 19 of offspring pregnancy, BP was measured via carotid catheterization and the blood and brains were collected for analyses. Results: IUGR Preg rats have elevated BP (116 ± 4.17 vs 100.6 ± 2.54 mmHg, p<0.02) and 8-isoprostanes (439.2 ± 13.61 vs 381.3 ± 26.10 g, ns), decreased circulating antioxidant capacity (AC) (0.33 ± 0.01 vs. 0.37 ± 0.01 mM Trolox/mg protein, p<0.01), and reduced body weight (330.1 ± 5.24 vs 350.3 ± 10.82 g, ns) compared to CON Preg rats. IUGR Preg rats have larger brains, suggesting brain swelling (5.38 ± 0.10 vs 4.95 ± 0.19 g/1000g BW, p<0.04). HSP-1 (186.1 ± 28.14 vs 100.0 ± 6.36 %HSP-1/protein/CON, p<0.04) and H2O2 (25.76 ± 2.95 vs 15.81 ± 4.56 μM/mg protein, ns), markers of ROS, are increased in the brains of IUGR Preg vs. CON Preg rats. Cerebral AC was slightly reduced (260.0 ± 33.14 vs 292.3 ± 13.91 uM Trolox/mg protein) and MnSOD (antioxidant) amounts were decreased (87.96 ± 3.43 vs 100.0 ± 2.84 %MnSOD/protein/CON, p<0.63). Conclusion: IUGR Preg rats have increased systemic and cerebral OS, as well as larger brain sizes which may lead to cerebral damage. In summary, pregnant daughters from hypertensive placental ischemic moms show symptoms of a preeclamptic-like phenotype, thus creating a new model of PE. Future studies will determine the role of maternal PE status and OS in the development of HTN in pregnant IUGR offspring.