bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of Activity Before or During Pregnancy on Fetal and Infant Heart Outcomes
Authors: May Linda E , Reoyo Olga R , Moyer Carmen M , Newton Edward R , Strickland Diana 
Published: November 2023

We hypothesized that exercise during pregnancy will have greater influence than exercise prior to pregnancy on improved offspring heart rate; this was tested by measuring fetal and infant heart rate. Women were classified into 4 groups: AA=active before and during pregnancy, AI=active before, inactive during pregnancy, IA= inactive before, active during pregnancy, and II= inactive before, inactive during pregnancy. Based on current guidelines, active was defined as ≥150min per week of moderate intensity exercise. Those not meeting criteria were classified as inactive. Fetal (36 wk) and infant (1 mo) heart rates were acquired via ECG and MCG recordings. Data from 83 uncomplicated pregnancies (AA=39, AI=13, IA=12, II=19) was analyzed. We found that fetuses from AA women had lowest heart rates of all groups, especially compared to fetuses of II women (p=0.002). In infant HR, we found significantly lower HR in infants exposed to exercise in utero relative to those not exposed with greatest differences in HR between AA and II groups (p=0.001). As we anticipated, we have found significantly lower fetal and infant heart rates in exercise‐exposed offspring regardless of women's activity prior to pregnancy. However, this dataset does not control for fetal/infant activity state, which may influence findings. These results further support the benefit of exercise as the primary mechanism for positive affects on fetal and infant heart rate. These data further support a prenatal programming effect on the fetal cardiac autonomic nervous system from maternal physiological events during gestation.Support or Funding InformationEast Carolina University StartUp funds
Chronic Flutamide Treatment Alters Intrarenal Renin Angiotensin System Expression in Intrauterine Growth Restricted Female Rats
Authors: Dasinger John Henry , Intapad Suttira , Rudsenske Benjamin R , Alexander Barbara T 
Published: November 2023

Intrauterine growth restriction (IUGR) programs an increase in blood pressure associated with early reproductive senescence in female IUGR rats at 12 months of age. Serum testosterone (T) levels are increased in female IUGR rats at this age mimicking the hormonal milieu of postmenopausal women (PMW). Testosterone is positively associated with blood pressure in PMW. Thus, our laboratory previously reported that chronic blockade of the androgen receptor with flutamide abolished hypertension in female IUGR rats. However, the mechanism remained unclear. Activation the renin angiotensin system (RAS) may be important in the etiology of hypertension in PMW. Therefore, for this study we tested the hypothesis that activation of the vasoconstrictor arm of the RAS would be attenuated via chronic blockade of the androgen receptor in female IUGR rats. Following a two week treatment with flutamide (8mg/kg/day) or vehicle, kidneys were harvested and separated into cortex and medulla. Cortical RNA was isolated then converted into cDNA. Real‐time PCR was performed using Bio‐Rad SYBR Green Supermix and iCycler using primers for renin, androgen receptor, angiotensin converting enzyme (ACE) and angiotensin converting enzyme 2 (ACE2). Levels of mRNA expression are reported for cycle threshold method. Intrarenal renin mRNA expression was increased 2.5 fold (2.6±0.65 vs. 1±0.42, P<0.05) in renal cortex of IUGR vs. control kidneys. Following flutamide treatment, renin mRNA levels were normalized in IUGR vs. control (1.03±0.6 vs. 0.7±0.4). Androgen receptor and ACE expression were similar in vehicle control and IUGR rats; flutamide treatment had no further effect. There was a significant reduction in the ACE2 in vehicle treated IUGR relative to vehicle treated controls (0.84±0.12 vs. 1±0.11, P<0.05); however, flutamide treatment had no further effect on ACE2 expression. We previously reported that intrarenal ACE2 expression was increased in normotensive female IUGR offspring in young adulthood. Yet, we observe a reduction in intrarenal ACE2 expression with age in female IUGR rats. Thus, these data indicate that T may contribute to the etiology of hypertension in female IUGR rats via activation of the RAS. Since T causes activation of the RAS, targeting the androgen receptor could be a potential therapeutic intervention for postmenopausal hypertension.Support or Funding InformationNIH: HL074927, HL51971, P20GM104357, AHA: GRNT19900004, 15PRE24700010
Effect of Aging on Kidney Function in Male Intrauterine Growth Restricted Rats
Authors: Newsome Ashley , Dasinger John Henry , Intapad Suttira , Davis Gwen , Alexander Barbara 
Published: November 2023

Epidemiological studies show a correlation between low birth weight (LBW), reduced nephron number, and an increased risk of kidney disease later in life. We hypothesized that LBW males would have lower nephron numbers and diminished kidney function compared to their age‐matched controls. To test this hypothesis, our lab performed a reduced uterine perfusion or sham surgery on day 14 of gestation in timed pregnant rats to induce intrauterine growth restriction (IUGR). Their male offspring were aged to 18 months. Metabolic studies were performed to collect 24‐hr albuminuria data. Rats were then instrumented with jugular catheters and allowed to recover overnight. FITC‐sinistrin was infused intravenously in conscious rats to calculate glomerular filtration rate (GFR) by transcutaneous clearance measurements, and the right kidney was harvested to calculate nephron number through a semi‐quantitative acid maceration technique. Albuminuria was remarkably high in both groups, but there was no significant difference in IUGR (206.6±29.2 mg/day) compared to control (286.3±50.7 mg/day)(n=12/group). GFR examined in a subset was not significantly decreased in IUGR (0.48±0.07) compared to control (0.69±0.11)(p‐value=0.16, n=4/group). Nephron number was not statistically different in IUGR (75,000±4,074) compared to control (96,400±8,298) although there was a trend towards significance (p‐value=0.055, n=4/group). These data indicate that males have kidney injury and a reduction in kidney function that is independent of developmental programming effects by 18 months of age. However, this does not provide evidence about the time course of development of kidney injury or the susceptibility of IUGR offspring to secondary renal insults. Therefore, one future aim is to measure kidney function in younger males to determine whether there is a difference in the age of onset of GFR reduction and albuminuria in these animals. We will also study the effect of uni‐nephrectomy as a second hit in the progression of renal injury.Support or Funding InformationNIH 074927, T32HL105324, AHA GRNT1990004
Reductions in βENaC and ASIC2 Induce Preeclampsia‐Like Symptoms in Pregnant Mice
Authors: Warrington Junie Paula , Granger Joey P , Ryan Michael J , Drummond Heather A 
Published: November 2023

Preeclampsia is a complex, multi‐organ, pregnancy‐specific condition characterized by new onset hypertension with or without proteinuria past the 20th week of gestation. The underlying pathophysiological mechanisms have not been fully elucidated. Beta Epithelial Na+ Channels (βENaC) and Acid Sensing Ion Channel 2 (ASIC2), members of the degenerin protein family, play important roles in vascular function including smooth muscle cell migration. We and others have shown that βENaC is also important for trophoblast migration. While βENaC is reduced in placentas from preeclampsia patients and a rat model of placental ischemia‐induced hypertension, it is not known whether reductions in degenerin proteins lead to altered placental function and cardiovascular abnormalities during pregnancy. Therefore, the purpose of this study was to determine if reductions in ASIC2 and βENaC contribute to preeclampsia‐like symptoms during pregnancy using a novel genetic mouse model initially generated by crossing ASIC2 null mice with mice with reduced levels of βENaC (βENaCm/m) (ASIC2−/− × βENaCm/m). In this study, adult virgin female mice were mated with age‐ and genotype‐matched males overnight and separated the following morning (day of separation considered gestational day one). Mice were weighed every other day and on gestational day 18.5, tissues were harvested for analysis. Pregnant ASIC2−/− × βENaCm/m mice gained significantly less weight during pregnancy (8.3 ± 0.7 vs. 14.0 ± 1.4g, p = 0.003), had increased fetal resorptions (29.1 ± 6.7 vs. 2.1 ± 2.1%, p = 0.002), and decreased number of live pups (3 ± 1 vs. 9 ± 1, p < 0.001) compared to wild‐type (WT) pregnant mice (n = 5–6 per genotype). However, both fetal (1.0 ± 0.1 vs. 0.8 ± 0.1g, p = 0.005) and placental (0.14 ± 0.00 vs 0.10 ± 0.01g, p < 0.001) weights were significantly higher in the pregnant ASIC2−/− × βENaCm/m mice compared to WT pregnant group. Additionally, pregnant ASIC2−/−× βENaCm/m mice had decreased circulating levels of vascular endothelial growth factor (VEGF; 122 ± 11 vs. 206 ± 22 pg/mL, p = 0.009) and modest elevations in blood pressure (113 ± 2 vs. 102 ± 4 mmHg, p = 0.02) compared to WT pregnant mice. These data indicate that pregnancy, superimposed on the ASIC2−/−× βENaCm/m background, produces preeclampsia‐like symptoms. Future studies will assess the relative role of ASIC2 and βENaC in mediating these changes during pregnancy.Support or Funding InformationNIH P20GM104357, P01HL051971, AHA 13POST16240000, and AHA20410022.
Modulation of Salt and Mineralocorticoid Sensitivity of Blood Pressure by the Circadian Clock Protein Per1
Authors: Solocinski Kristen , Wen Xuerong , Cheng Kit‐Yan , Lynch Jeanette , Wingo Charles S. , Cain Brian D. , Gumz Michelle L. 
Published: November 2023

Increasing evidence demonstrates that circadian clock proteins are important regulators of physiological function. Consistent with this concept, we previously showed a role for the clock protein Per1 in the regulation of blood pressure. Global Per1 knockout mice on the salt‐sensitive 129/sv mouse strain exhibited dramatically lower mean arterial pressure (MAP) compared to wild type controls under standard conditions (Stow et al. Hypertension 2012). Interestingly, the normal circadian rhythm of blood pressure was not affected by loss of Per1 in this mouse model. The goal of the present study was to determine the effects of a high salt diet plus mineralocorticoid on Per1‐mediated blood pressure regulation in a salt‐resistant mouse model, C57BL6. As expected, MAP in wild type mice was not affected by a high salt diet (4%) plus injection with the long‐acting mineralocorticoid deoxycorticosterone pivalate (DOCP). In contrast, Per1 knockout mice exhibited significantly increased MAP (by 10 mm Hg, p<0.01) in response to a high salt diet plus DOCP. The day/night ratio of MAP in wild type mice was unchanged by high salt plus DOCP treatment. Conversely, this treatment caused Per1 knockout mice to completely lose the expected decrease or “dip” in blood pressure during the day compared to the night. Thus, loss of Per1 increased sensitivity to the high salt plus DOCP treatment and also resulted in a non‐dipper phenotype in this hypertensive model. Together these data support an important role for the circadian clock protein Per1 in the modulation of blood pressure in a high salt/mineralocorticoid model of hypertension.Support or Funding InformationThis work was supported by NIH DK085193 and DK098460, the ASN Foundation for Kidney Research to MLG, 2T32HL083810 to KS, and NIH DK082680 to BDC and CSW.
Loss of Protein Kinase C Alpha Disrupts Mean Arterial Pressure and Diurnal Rhythm
Authors: Wynne Brandi Michele , Molina Patrick , Klein Janet , Hoover Robert S 
Published: November 2023

The sodium‐chloride cotransporter (NCC) is an essential regulator of sodium transport in the distal convoluted tubule (DCT). As such, functional aberrations will lead to dysregulation of sodium homeostasis and blood pressure. Although this role is well accepted, the mechanisms accounting for increased distal nephron sodium reabsorption is not completely understood. Previously published data from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study revealed that a single nucleotide polymorphism (SNP) in PKC‐α increases sensitivity to thiazide diuretics. To date, it is unknown whether this SNP is a gain or loss of function of PKC‐α. To investigate whether PKC‐α may be altering blood pressure via NCC, PKC‐α KO (PKC KO) and PKC Control (CTL) mice were used to measure blood pressure via radiotelemetry after normal and high salt (HS, 4%) dietary manipulations and Western blot analysis performed using kidney lysates. Using radiotelemetry (DSI) measurements obtained over an active and sleeping time periods, we report a significant decrease in mean arterial pressure (MAP) in the PKC KO mice as compared to control at baseline (111±1.3mmHg vs 120±2.4mmHg, n=12–16, p<0.001). When comparing active vs. sleeping MAP, PKC KO mice had depressed MAP during both time periods, yet blood pressure differences (day vs. night) double during active periods (5.4±1.3mmHg PKC KO vs. 10.9±3.9mmHg PKC CTL, n=6–7). These differences were abolished with HS chow feeding (17.3mmHg PKC KO vs. 16.1mmHg PKC CTRL, n=4). To determine a possible mechanism for this phenomenon, whole kidney lysate was used to assay for total NCC protein. Total NCC protein was significantly increased in PKC KO mice at baseline, and continued during HS chow feeding, as compared to PKC CTL. In addition, PKC KO mice exhibited a diuresis with both normal and HS feeding. Our data suggest that lack of PKC‐α leads to decreased MAPs and diuresis, which may lead to increased total NCC expression to compensate. In addition, PKC KO mice exhibited an aberrant diurnal rhythm, which was recovered with HS diet suggesting that PKC‐α may be necessary to maintain sodium homeostasis.Support or Funding InformationNIDDK085097‐ RSH 2T32DK7656‐21 Emory Renal Division‐BMW
Blood pressure regulation under low K+ intake depends on the H,K‐ATPase type 2
Authors: Crambert Gilles , Salhi Amel , Lamouroux Christine 
Published: November 2023

In industrialized countries, a large part of the population has a low daily K+ intake, which appears to be correlated with the development of salt‐sensitive hypertension. Among many processes, adaptation to K+ restriction involves the stimulation of H,K‐ATPase type 2 (HKA2) in the kidney and colon. In this study, we investigated whether HKA2 also contributes to the determination of blood pressure (BP). We compared wild‐type (WT) and HKA2‐null mice (HKA2 KO), and showed that after 4 days of K+ restriction (LK diet), WT remain normokalemic (3.7±0.1 mM) and normotensive (112 ±3 mm Hg) whereas HKA2 KO mice exhibit hypokalemia (3.2±0.1 mM) and hypotension (104±2 mm Hg). To elucidate the mechanism explaining the variations in BP between both strains, we measured, mRNA and protein expression as well as in vivo activity of NCC and ENaC. In WT mice under LK diet, we observed a switch between electrogenic (downregulation of ENaC activity and expression) and electroneutral (stimulation of NCC activity and expression) Na+ reabsorption. In these mice, the renal Na+ excretion remained similar to that measured under normal condition. Regarding HKA2 KO mice under LK diet, their NCC is not stimulated inducing a renal loss of Na+ and a decrease of the extracellular volume (by 20%). This increase of natriuresis in HKA2 KO mice under LK diet is correlated with 1/ the increase of PGE2 excretion (by 100% vs WT mice) and 2/ the observed renal resistance to vasopressin and the lower protein expression of AQP2 (by 50% vs WT).Interestingly, the ability to stimulate NCC under LK diet renders the WT mice more sensitive to concomitant increased intake of Na+. Indeed, BP of WT mice increased by 15 mm Hg when given a salt load along with the K+ restriction. In contrast, the BP of HKA2 KO mice does not increase under LK diet and salt loading. We conclude that the presence of an activated HKA2 is required under K+ restriction not only to limit the decrease in plasma [K+] but also to maintain a normal BP level when salt intake is rather low rather low. However, when salt intake increases, the absence of the HKA2 appears to protect against the development of salt‐sensitive hypertension.
Role of Kir5.1 (Kcnj16) Channel in the Control of Potassium Homeostasis in the Kidney
Authors: Palygin Oleg , Levchenko Vladislav , Geurts Aron , Staruschenko Alexander 
Published: November 2023

The inwardly‐rectifying potassium (K+) channels (Kir), Kir4.1/Kir5.1 (Kcnj10/Kcnj16) are critical channels responsible for the recycling of K+ in the distal nephron as well as regulation of basolateral membrane potential. Human mutations in KCNJ10 and KCNJ16 are associated with renal pathologies characterized by salt‐wasting, renal tubulopathy and hypokalemia (EAST/SeSAME and Gitelman syndromes) as well as cardiac phenotypes such as Brugada syndrome). The Kir4.1/Kir5.1 heteromeric channel is expressed on the basolateral side of distal convoluted tubule (DCT) cells and the principal cells of the cortical collecting duct (CCDs). Immunohistochemistry analysis of Dahl salt‐sensitive (SS) rats showed increased Kir5.1 abundance in the CCD compared to the DCT. Moreover, expression of Kir5.1 in both segments was significantly upregulated after 3 weeks of high salt diet (4% NaCl), showing a direct correlation between the development of salt sensitive hypertension and basolateral K+ channel function. To further explore the role of this channel in salt‐sensitive hypertension, we have created a loss‐of‐function mutation in Kir5.1 in the Dahl SS rat (SS‐Kcnj16em1Mcwi) using zinc‐finger nucleases. Overall, Kir5.1 loss‐of‐function mutation in the SS rat induced a renal phenotype characterized by hypokalemia (2.1±0.2 vs 4.3±0.1 mmol/L (mutant vs SS)), low aldosterone level (245.4±26.5 vs 1050±100 pg/ml), salt wasting (FEK+ 30.3±3.1 vs 5.8±0.6; FENa+ 0.42±0.06 vs 0.19±0.03; FEMg2+ 15.8±1.3 vs 6.1±0.9 %) and decreased mean arterial blood pressure (91.3±1.8 vs 104.7±5.5 mmHg). Furthermore, the absence of the Kir5.1 from distal nephron resulted in a compensatory increase of Kir4.1 protein abundance. IHC analysis of Kir4.1 localization revealed a rerouting from its expected location in the basolateral membrane of CCD and DCT tubules to the cytosol instead. We also found that loss‐of‐function mutation of Kir5.1 triggered upregulation of both total and phosphorylated forms of the NCC and NKCC2. In contrast, we were not able to identify any changes in the expression of ENaC subunits. Increasing the salt content of the diet from 0.4 to 4% triggered sodium and potassium excretion in Kir5.1 mutants, which resulted in a rapid reduction of blood K+ to critically low values (1.36±0.04 vs 2.1±0.1mmo/L (HS vs LS)). Na+ blood concentrations (141.6±0.5 vs 139.2±1.5 mmo/L) were unchanged between these two groups. This severe hypokalemia resulted in high mortality rate with most animals dying within 24 hours. These data demonstrate the critical role of renal basolateral Kir4.1/Kir5.1 channels in potassium handling, and identify them as a potential pharmacological target for the treatment of the imbalanced potassium homeostasis.Support or Funding InformationSupported by Advancing a Healthier Wisconsin Research and Education Program #9520217 and HL122662
Losartan May Reduce the Effect of Fluid Resuscitation Following Haemorrhage in Rats
Authors: Melville Jacqueline M , Hultström Michael 
Published: November 2023

Acute kidney injury (AKI) affects 2% of hospital in‐patients. AKI is particularly a concern following surgery, as patients that require transfusions during surgery are at a greater risk for AKI, indicating haemorrhage as a cause. Angiotensin II AT1‐receptor blockers (ARB) are thought linked to postoperative AKI due to their hypotensive actions; as a result ARBs are often discontinued before surgery. We have previously found that there is no difference between losartan‐treated and control rats in Δ renal blood flow (RBF), Δ renal vascular resistance (RVR) and Δ kidney oxygenation in response to haemorrhage, indicating that ARBs may not be detrimental following haemorrhage. However, the impact of ARBs on fluid resuscitation and norepinephrine after haemorrhage is less well studied.Wistar rats were treated with either control (n = 4) or the ARB losartan (60 mg/kg/day in drinking water, n = 6) for 7 days. Rats were anaesthetised with thiobutabarbital and surgery was performed for the insertion of catheters and a flow probe around the renal artery followed by a controlled haemorrhage of 20% blood volume. Five minutes following haemorrhage fluid resuscitation began (volume replacement with ringer's solution) over a period of 10 minutes. Mean arterial blood pressure (MAP) and RBF were measured before haemorrhage, and throughout fluid resuscitation.The effect of fluid resuscitation on blood pressure (ΔMAP) tended lower in losartan (9.71±2.7 mmHg) compared to control (21.5±5.7 mmHg, p = 0.06). There was no statistical difference between ΔRBF or ΔRVR following fluid resuscitation between losartan (1.6±1.09 ml/min and −120.7±59.0 mmHg/ml/min, respectively) and control (1.2±0.16 ml/min and −142.2±116.3 mmHg/ml/min).The response to a bolus dose of 0.08μg/kg norepinephrine after haemorrhage and resuscitation was not different between losartan and control rats for the area under curve (AUC) of blood pressure (15416±2404 vs. 12634±2472mmHg.s), RBF AUC (64.52±19.84 vs. 155.3±65.46 ml/min.s) or RVR AUC (75546±32617 vs. 88997±42130 mmHg/ml/min.s).These preliminary data may demonstrate that losartan, an AT1‐receptor blocker, reduces MAP recovery following fluid resuscitation but does not affect the response to norepinephrine post‐haemorrhage.Support or Funding InformationSwedish Society for Medical Research
Intrarenal Hypoxic Mesenchymal Stem Cells Transplantation Enforces Homing and Paracrine Effects to Ameliorate Anti‐Thy1.1‐Induced Nephritis in Rats
Authors: LAI YI‐AN , Chang Hao‐Hsian , Hsu Shih‐Ping , Chien Chiang‐Ting 
Published: November 2023

In acute glomerlonephritis, activated resident cells or infiltrated inflammatory cells‐derived oxidative stress evoked GRP78‐mediated endoplasmic reticulum stress, Bax/Bcl‐2 family‐related apoptosis and Beclin‐1/LC3‐II‐mediated autophagy leading to glomerular injury. Mesenchymal stem cells (MSC) provide excellent self‐renewal and proliferation ability. In addition, MSC may release high levels of growth factors, cytokines and prostaglandins in the microenvironment by the paracrine mechanism to enhance cell proliferation, survival and angiogenesis to repair injuried tissue. Under hypoxic condition, MSC (HMSC) can not only prevent senescence but also increase differentiation efficiency. We aimed to evaluate the therapeutic effects and mechanisms of MSC or HMSC on anti‐thy1.1‐induced glomerulonephritis in the rats. Our results found that intrarenal arterial administration of MSC or HMSC (1×105, 2×105, 5×105 cells) can successfully implant in the glomeruli and proximal and distal tubules. Anti‐thy1.1 induced glomerulonephritis by the appearance of mesangial cell lysis, increase of collagen by Masson stain, collagen IV expression, ED‐1 infiltration, GRP78/endoplasmic reticulum (ER) stress, Bax/Bcl‐2/Caspase 3/PARP‐mediated apoptosis, Beclin‐1/LC3 II‐mediated autophagy and elevated urinary protein levels in nephritic rats. HMSC was more efficient than MSC significantly and dose‐dependently in reducing PAS‐injuried score, ED‐1 infiltration, GRP78/ER‐stress Bax/Bcl‐2/Caspase 3/PARP‐mediated apoptosis, Beclin‐1/LC3 II‐mediated autophagy, Masson stain, collagen IV expression and elevated urinary protein levels in nephritic rats. HMSC was more efficient than MSC in the reappearance of OX‐7 stain (Thy1.1 stain) in the nephritic glomeruli. Our results indicate that HMSC through higher efficiency in homing and paracrine effects attenuate autophagy, apoptosis, ER stress, inflammation and glomerular sclerosis in acute nephritis.Support or Funding InformationDepartment of Life Science, National Taiwan Normal University, Taipei, Taiwan, ROC