bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 164: Impact of Sex and Race on the Likelihood of Mortality, Cardiology Consultation, and Coronary Angiography Among Hospitalized Patients Evaluated With Cardiac Troponin
Authors: Winchester David E , Estel Christopher , Kline Kristopher , Taasan Sean , Park Ki , Zhang Jingnan , Shuster Jonathan
Published: June 2021

Introduction:
Serum troponin (Tn) is a highly sensitive test useful in diagnosing acute myocardial infarction. Elevated Tn is associated with higher mortality and greater use of cardiovascular services. The effect of sex and race on these observations has not been well characterized. We hypothesize that sex and race will be independent predictors of cardiology consultation and cardiac catheterization.

Methods:
We analyzed adult patients hospitalized between 2012 and 2015 who had Tn testing. Patients were compared in 2 cohorts: those with and those without elevation in Tn. We extracted data on demographics, self-reported race, medical history, new inpatient diagnoses, Charlson comorbidity index (CCI), and mortality (up to 3 years). We developed a Cox proportional hazard model for mortality and used logistic regression to determine associations with cardiology consultation and cardiac catheterization.

Results:
Of the 26,663 included, 22.0% were black, 50.1% were women, 9.8% had diabetes, and 6.4% had pre-existing coronary disease. Cardiac catheterization was performed on 1,800 (6.8%), 3,672 (13.8%) had a cardiology consult, and 4,962 (18.6%) had elevated Tn. Among the variables associated with cardiology consultation were elevated Tn (odds ratio [OR] =3.44, 95% confidence interval [CI] 3.19-3.72, p<0.0001), male sex (OR=1.29, 95% CI 1.20-1.39, p<0.0001) and black race (OR=0.85, 95% CI 0.77-0.93, p=0.0006). Cardiac catheterization was associated with elevated Tn (OR=8.16, 95% CI 7.34-9.06, p<0.0001), male sex (OR=1.45, 95% CI 1.31-1.61, p<0.0001), CCI >4 (OR=0.44, 95% CI 0.35-0.54, p<0.0001), and black race (OR=0.72, 95% CI 0.63-0.82, p<0.0001). A total of 4,697 patients died during follow-up. Elevated Tn (hazard ratio [HR] =2.05, p<0.0001), male sex (HR=1.14, p<0.0001), and CCI >4 (HR=3.33, p<0.0001) were associated with a higher risk of death, while risk among black patients was lower (HR=0.86, p<0.0001).

Conclusion:
As observed in other investigations, elevated Tn is associated with a higher risk of mortality, cardiac catheterization, and cardiology consultation. We observed that men were more likely to undergo catheterization and consultation, while black patients were less likely to have either. Further investigation into reasons for the observed disparities is warranted.
Abstract 182: Heart Transplantation Patients in the Medicare Population: Outcomes, Costs and Readmission Rates
Authors: McCarthy Fenton , Graves Desmond , Savino Danielle , Chin Amanda , Spragan Danielle , Dibble Taylor , Hoedt Ashley , McDermott Katherine , Dufendach Keith , Groeneveld Peter , Bavaria Joseph , Szeto Wilson , Desai Nimesh
Published: June 2021

Objective:
The average age of heart transplant recipients in the United States has been increasing over the past decade. The effect of age on outcomes following heart transplantation, including cost and readmission has yet to be thoroughly evaluated.

Methods:
All Medicare fee-for-service patients undergoing heart transplantation between 2008 and 2013 were included in the study. Denominator files were used to collect patient demographics and mortality. Kaplan-Meier survival estimates and Cox Proportional Hazards models were used for overall survival analysis.

Results:
A total of 4431 heart transplant patients were included in this study. Patients were broken down into categories of age <60, 60-69, and >70. Patients >70 were more likely to be male, white and have CAD and ischemic cardiomyopathy than patients <60. Multivariable cox survival model showed ECMO (HR 9.5, 95% CI 7.7 - 11.6, p < 0.01) and liver disease (HR 1.6 95% CI 1.2 - 2.2, p < 0.01) were associated with increased long-term mortality (p<0.01 and p=0.02, respectively). There was a significant difference in ECMO usage between patient groups with 6% of patents > 70, 4% of patients 60-69, and 3% of patients < 60 requiring ECMO (p=0.05). There was no significance was seen in 30 day mortality rates among between patients > 70 (5%) and patients < 70 years of age (5% ), p=0.83. Additionally, there was no difference between ICU lengths of stay, 30- and 90-day readmission rates (p=1.0 and p=0.72 respectively), and hospital length of stay (p=0.35) (Table 1).

Conclusions:
Among Medicare patients undergoing heart transplantation, those over the age of 70 had no difference in terms of survival and cost utilization compared to younger patients. Heart transplantation programs are doing a good job of selecting older patients in order to maintain these outcomes. Age was associated with increased use of ECMO, and ECMO adversely affected long-term survival.
Abstract 195: Statin Use and Its Facility Level Variation in Patients With Ischemic Cerebrovascular Disease: Insights From the Department of Veterans Affairs
Authors: McBride Cameron L , Akaroyd Julia , Ramsey David J , Nambi Vijay , Nasir Khurram , Michos Erin D , Birtcher Kim K , Morris Pamela B , Bittner Vera A , Ballentyne Christie M , Peterson Laura A , Virani Salim S
Published: June 2021

Background:
The 2013 ACC/AHA cholesterol guideline recommends high-intensity statin therapy in patients 75 or younger and moderate-intensity statins in patients > 75 years with atherosclerotic cardiovascular disease including those with ischemic cerebrovascular disease (ICVD). Statin prescribing patterns and their facility-level variation in patients with ICVD are unknown.

Methods:
We examined the frequency and facility-level variation in the use of any and correct intensity statins in patients with ICVD (ischemic stroke or carotid arterial disease) who received primary care in 130 facilities across the Veterans Affairs (VA) health care system with or without concomitant ischemic heart disease (IHD) or peripheral artery disease (PAD). We then calculated median rate ratios (MRR) adjusted for patient demographic factors to assess the magnitude of facility-level variation in statin prescribing patterns for comparable patients.

Results:
Among 339,771 ICVD patients, 182,231 (53.6%) had ICVD without IHD (with or without PAD) and 163,730 (48.2%) had ICVD without IHD or PAD. Rates of statin use in the entire ICVD group, patients with ICVD without IHD, and ICVD alone were 78.1%, 70.9% and 69.9%, respectively. Median facility-level rates of any statin use were 78.1% (IQR 75.5-80.7), 70.7% (67.9-73.8) and 69.9% (66.9-73.1), respectively. Correct intensity statins were prescribed among 40.2% of the entire ICVD group, 30.5% with ICVD without IHD, and 29.6% with ICVD alone. Median facility-level rate of correct statin use in all ICVD patients was 39.1% (35.8-43.9), 29.9% (26.0-34.6) for patients with ICVD without IHD and 29.0% (25.4-33.7) in those with ICVD alone.Calculated MRRs reflect approximately 22% variation among two facilities treating two identical ICVD patients with statin therapy and a 27-28% variation in identical ICVD patients for correct statin intensity (Table).

Conclusions:
The use of statin and especially guideline-recommended statin intensity is suboptimal in ICVD patients, especially patients without concomitant IHD or PAD. There is significant facility-level variation in receipt of guideline directed statin therapy in ICVD patients. Interventions are needed to improve guideline directed moderate to high-intensity statin use and reduce variation in care in this high risk group.
Abstract 202: Impact of Diagnosis Name Changes in the Comprehensive Medical Expenses Payment System on Medical Expenses in Japan
Authors: Shirakawa Toru , Matsumoto Hiroshi
Published: June 2021

In Japan, medical expenses are increasing, which has been shifting from 36.6 trillion yen in FY 2010 to 40.0 trillion yen in FY 2010. 1 The system changed to the conventional payment method, and a comprehensive medical expenses payment system (DPC) centered on patients (diseases) was introduced. Medical expenses according to this method are calculated from the main disease name diagnosed at the time of admission. Therefore, it depends on the accuracy of the diagnosis name. Regarding the relevance of this diagnosis, there is one lesson from the trend of the death cause statistic of our country. In this study, we aimed to estimate the effect on medical expenses when the diagnosis name change similar to the death causes statistics around 1995 occurred, using DPC data. The targeted DPC data relates to discharged patients from April 2013 to March, 2013 DPC Hospital Group I 80 DPC Hospital II Group 90 DPC Hospital III Group 1327 Hospital. Diagnosis group for each diagnosis group classification for each diagnosis group classification. Based on the average number of days of hospitalization for classification names, in-hospital medical points were calculated, multiplied by the number of cases and multiplied by 10 to make medical cost corresponding to the relevant diagnosis group classification name. Next, heart disease, cerebrovascular disease, and malignant tumor were defined for each diagnosis, and the number of medical cases, the medical expenses per capita, the total medical cost, and the average number of hospital days were calculated for each diagnosis. We estimated the change in medical expenses assuming that 20% of cases of heart disease were moved to cerebrovascular disease and malignant tumor by 10% each. This change in DPC medical expenses was estimated as the change in medical expenses by multiplying the total of DPC medical expenses by the ratio of medical expenses of 39.3 trillion yen in fiscal year 20 of medical expenses in Japan in fiscal year 2013. The sum total of DPC medical expenses for Heisei 20 years was 2.03 trillion yen. The DPC medical expenses were 2.21 billion yen lower after the movement than before the diagnosis was moved. Based on the above, it is estimated that medical expenses in Japan will decrease by 40.9 billion yen when the diagnosis of heart disease moves to cerebrovascular disease and malignant tumor by 10% each. It is necessary to examine the possibility of suppression of medical expenses in more detail by expensive treatment and aggregation by age group.
Abstract 222: Use of a Decision Support Tool for Ischemic Stroke Treatment in a Telehealth System
Authors: Summers Debbie , Gialde Elizabeth , Spertus John A , Decker Carole
Published: June 2021

Background:
Alteplase does not uniformly benefit patients with acute ischemic stroke (AIS). Variable times since symptom onset, age, comorbidities and symptom severity add much uncertainty to physicians’ ability to knowledgeably individualize clinical decision-making. This contributes to the recent controversy regarding ACEP-authored expert guidelines which support presentation of risks and benefits and a process of shared decision-making. We previously developed the RESOLVE decision support tool for generating personalized estimates of the benefits and risk of alteplase and developed implementation strategies for both the Emergency Department (ED) and Telehealth settings. This study was a survey of physicians in rural hospitals within a large stroke network to quantify physician’s satisfaction and confidence in treating AIS after having access to the RESOLVE tool.

Methods:
To provide rural ED physicians access to the RESOLVE decision support tool prior to the administration of alteplase for AIS, nurses at a centralized Telehealth system were trained to enter the data elements required to run the RESOLVE model and fax the tool to the rural hospital immediately, while the provider was waiting for a neurologist’s consultation from the comprehensive stroke center. We then conducted semi-structured interviews of rural hospital physicians who used the tool as soon as possible. We interviewed 14/28 physicians at 7 critical access hospitals, 6 rural community hospital and one urban public that used the RESOLVE tool in decision making during a 6 month pilot.

Results:
Providers strongly agreed the tool was helpful in discussing potential risks and benefits with the patient or family. Having the knowledge of the individualized patient risk of hemorrhage, and being able to inform the patient/family, was a theme that emerged from qualitative analyses of the interviews.

“Knowing the risk of hemorrhage was only 3% made me more comfortable giving IV tPA”
- ED Physician, Critical Access Hospital

“[I] used it to discuss the risk of hemorrhage with the patient/family. That was very helpful.”
- ED Physician, Urban Public Hospital

“…used it to discuss the benefits and risks, having it helped me to know what to discuss with the patient/family.”
- ED Physician, Rural Community Hospital

Study limitations included the difficulty in interviewing physicians due to 12-hour work shift and those practicing as a locum tenens. Additionally, the timing and fax location was a limitation in some physicians seeing the tool prior to prior to treatment.

Conclusions:
The preliminary results showed the rural hospital providers saw value in the RESOLVE tool while discussing the risks and benefits with patient/family. Future strategies would include process changes to expedite the faxing of the RESOLVE tool.
Abstract 233: Practice Process Variability and Outcomes, Relation to Interventionalist Volume
Authors: Lawson William E , Wilbert Lisa A , Gumersell Kellie , Horbatuk Elisa , Leonard Theresa , Dorney Anna , Gruberg Luis , Mani Anil , Parikh Puja , Marmora Joseph
Published: June 2021

Background:
For the hospital, the cardiac catheterization lab is a high risk, high volume, high cost center. With the evolving imperative to provide value over volume, cardiac catheterization lab utilization, processes, and outcomes are an increasing focus of both internal and external scrutiny on an individual operator and aggregate basis. A hospital initiated multidisciplinary task force reviews real time and quarterly data from the NCDR and New York State to provide operator and cath lab managerial feedback, modify practice, and to assess progress. Ongoing interventions include; worksheets, EMR and Cath Lab templates, timely data review and feedback to managerial staff and operators.

Methods:
Stony Brook University has an open Cardiac Cath Lab with services provided by 5 full time faculty and 12 voluntary (private practice) interventional cardiologists. Using internal, NYS [2009-2015], and 2015 NCDR data, utilization, processes, and outcomes of high volume [HV] operators [>100 PCI/yr] and those with a disproportionate rate of cath to PCI conversions [>50%] were compared to lower volume [LV] and low conversion rate operators.

Results:
High volume operators [6] performed an average of 171 interventions compared to an average of 36 for LV operators [11]. Cases rated appropriate increased from 26% (102 of 391) in 2010 to 96.4% (1448 of 1502) in 2015. Cases rated inappropriate decreased from 24.8% (97 of 391) in 2010 to 1.0% (15 of 1502) in 2015; HV operators 0.5% versus 2.2% LV operators in 2015. The cases rated uncertain also decreased from 49% (192 of 391) in 2010 to 2.6% (39 of 1502) in 2015; HV operators 1.6% versus 5.1% for LV operators in 2015. This is statistically significant with p < 0.05 by chi-square. Process indicators of stent utilization/case [1.8 vs 1.6] and contrast use [179 vs 166 cc/case] were similar in HV and LV operators with an increase in fluoroscopy times [20.2 vs 18.3 min], Total Area Dose [11,017 vs 9,154], Skin Dose 1,759 vs 1,536] in the LV operators. Bleeding complications were higher [5.8% vs 2.1%] in HV operators and mortalities were confined to the HV operators and those performing STEMI interventions.

Conclusions:
A multidisciplinary task force is an effective method of targeting multiple variables impacting on cath lab value metrics. Marked progress has been made towards the consistent and appropriate use of cardiac catheterization and angioplasty. The highest rates of cath-PCI conversion, bleeding complications and mortality were for HV full time cardiologists, providing 7x24 coverage for STEMI interventions and caring for a disproportionate number of ACS patients. Initiated processes, oversight and feedback changes have effectively minimized process and potential outcome differences between high and low volume operators.
Abstract 004: Aberrant CD4
+
T Cell Function in Stroke-prone Hypertensive Rats Due to a Mutation in Stim1
Authors: Dhande Isha S , Mamenko Mykola , Zhu Yaming , Pochynyuk Oleh , Wenderfer Scott , Braun Michael , Doris Peter
Published: June 2021

The genetic mechanism of end organ injury in hypertension may involve gene variation in genes participating in inflammation and its regulation. We identified a novel truncating mutation in the hypertensive end organ injury-prone spontaneously hypertensive rat (SHR-A3/SHRSP) line affecting the C-terminus of STIM1, a protein involved in the store-operated Ca
2+
entry (SOCE) pathway. The genomes of injury-resistant SHR lines, including SHR-B2 used here, encode the ‘wild-type’ STIM1. SOCE is required by T cells to activate the transcription factor NFAT and regulate T cell proliferation and cytokine production. T cell receptor (TCR) stimulation depletes intracellular Ca
2+
stores, activates the ER Ca
2+
-sensor STIM1 and results in SOCE. We tested the effect of STIM1 mutation on lymphocyte SOCE and found it was dramatically reduced in SHR-A3, but not in SHR-B2 (maximal [Ca
2+
]
i
: 150.5±34.9 vs 521.5±42.6 nM, p<0.0001). Flow cytometric analysis of circulating T cell subsets revealed comparable levels of CD4
+
and CD8
+
T cells in both lines, however circulating CD4
+
CD25
+
FoxP3
+
T
regs
were reduced in SHR-A3 compared to SHR-B2 (4.34±0.59 vs 7.12±0.33%, p=0.01). TCR-induced lymphocyte proliferation was similar in both SHR-A3 and SHR-B2. T cell cytokine production in response to TCR stimulation was markedly impaired CD4
+
T cells from SHR-A3 compared with SHR-B2 (IL-2: 168 ±83.4 vs 1385±377.0 pg/mL, p=0.01; IFNγ: 235±69.5 vs 2119±434.7 pg/mL, p=0.002). IL-2 and IFNγ production was completely inhibited by Pyr6, an inhibitor of Stim1-dependent SOCE. However, circulating levels of IL-2 and IFNγ were not different between the two lines. Based on our findings, we conclude that TCR-mediated effector signaling is impaired due to defective SOCE in SHR-A3 rats. Defects in SOCE in SHR-A3 attributable to STIM1 mutation alter T cell function, reduce T
reg
numbers and may disturb regulatory interactions between T cells and other immune cells involved in end organ injury.
Abstract 007: TRPM7-kinase Modulates Renal and Splenic Macrophage and T-lymphocyte Infiltration in Aldosterone-salt-induced Hypertension
Authors: Rios Francisco J , Hood Katie Y , Harvey Adam , Neves Karla B , Anyfanti Panagiota , Nosalski Ryszard , Camargo Livia L , Montezano Augusto C , Touyz Rhian M
Published: June 2021

TRPM7 is a Mg2
+
channel linked to a kinase domain important in cell proliferation and survival. We demonstrated that cells deficient in TRPM7-kinase domain are prone to aldosterone (aldo)-induced oxidative stress and inflammation. Here, we investigated whether TRPM7-kinase plays a role in inflammatory responses in aldo-induced hypertension. Wild-type (WT) or heterozygote TRPM7-kinase domain (TRPM7+/-) mice were infused with aldo (600μg/Kg/day - osmotic minipumps) and 1% NaCl in the drinking water (aldo-salt) for 4 weeks. Inflammatory responses were evaluated by examining T cells (CD4+ and CD8+) and macrophages (M1- and M2-phenotype) infiltration in kidneys and spleens, using flow cytometry. Gene and protein expression was assessed by real-time PCR and immunoblot respectively. ROS was evaluated by lucigenin chemiluminescence. Aldo-salt increased kidney mass and urinary levels of albumin, Ca
2+
, Mg
2+
and K
+
, similarly in WT and TRPM7+/- (p<0.05 vs controls). Kidneys from TRPM7+/- mice presented a higher total number of inflammatory infiltrated cells (0.87x10
6
vs WT 0.22x10
6
cells/g), TCD4+ cells (27%
vs
WT 19%), and macrophages (47% vs WT 31%) (p<0.05 vs controls). Kidneys from WT aldo-salt showed increased ROS production (1.7-fold) and Nox2 (2-fold) protein expression (p<0.05 vs control) and presented similar cell infiltration to TRPM7+/- mice. Kidneys from TRPM7+/- aldo-salt show increased M2-macrophages CD206+ (4.3% vs WT 2.3%) and mRNA expression for the anti-inflammatory cytokine IL-10 (55% vs WT), whereas decreased the expression of the pro-inflammatory TNFα (30% vs WT) and Nox2 protein (1.8-fold). Spleen mass was increased by 40% only in WT aldo-salt. Spleens from untreated TRPM7+/- showed increased infiltrated inflammatory cells (3.7x10
8
vs WT 2.0x10
8
cells/mg). Splenic macrophages were higher in untreated TRPM7+/- (8.8% vs WT 5.9%) and presented an increase in CD206 M2-marker (16% vs WT 7%), higher TCD4+ (68%
vs
WT 50%) and TCD8+ (26%
vs
WT 17%), values that were similar to WT aldo-salt. Our data provide insights into the importance of the TRPM7-kinase domain in the immune system activation, which when down regulated provokes an increase in inflammatory cell infiltration in kidneys and spleens in aldo-salt-induced hypertension.
Abstract 009: Genetically Modified Probiotics for Oral Delivery of Angiotensin-(1-7) Confers Protection Against Pulmonary Hypertension
Authors: Cole Jeffrey Colleen , Shenoy Vinayak , Verma Amrisha , Aquino Victor , Kumar Ashok , Liang Zhibing , Li Qiuhong , Katovich Michael , Raizada Mohan
Published: June 2021

Background:
Previous studies have established that activation of the members of the vasoprotective axis of the renin-angiotensin system [Angiotensin Converting Enzyme 2 (ACE2) or Angiotensin-(1-7) (Ang-(1-7))] prevents and arrests progression of pulmonary hypertension (PH) pathophysiology. Our objective in this present study was to generate a probiotic containing Ang-(1-7) and test the hypothesis that oral administration of such a probiotic would provide cardiopulmonary protection against PH.

Methods:
In this study, we genetically modified the commensal bacterium
Lactobacillus paracasei
(LP), commonly found in the gut and used as a probiotic, to serve as a live vector for the oral delivery of Ang-(1-7) and investigated its therapeutic potential in attenuating PH. The vectors pTRKH3-
ldh
-SP-GFP or pTRKH3-
ldh
-SP-Ang-(1-7) were introduced by electroporation into LP. PH was induced by a single injection of monocrotaline (MCT; 50 mg/Kg s.c) in rats. A subset of animals was orally gavaged every other day for four weeks with 1x10
9
CFU of LP, LP secreting GFP (LP-GFP), or LP secreting Ang-(1-7) (LP-A).

Results:
Oral feeding of LP-A significantly reduced MCT-induced right ventricular systolic pressure (RVSP) by 43% (Control: 27±1; MCT: 76±8; MCT+LP: 56±6; MCT+LP-GFP: 59±7; MCT+LP-A: 43±3 mmHg) and RV hypertrophy by 33% (Control: 0.25±0.01; MCT: 0.6+0.02; MCT+LP: 0.48±0.04; MCT+LP-GFP: 0.48±0.04; MCT+LP-A: 0.41±0.03). Moreover, LP-A feeding restored cardiac contractility (Control: 2070±95; MCT: 3133±295; LP-A: 2060±119 mmHg/s) and attenuated myocardial fibrosis. These beneficial effects on the cardiopulmonary system were associated with profound changes in gut pathology. MCT-induced PH was associated with an increase in ileum villus length and thickening of proximal colon, and a decrease in goblet cells/villus area, all of which indicate intestinal injury and altered immune status. However, these parameters were significantly attenuated by oral feeding of LP-A.

Conclusions:
Oral administration of a genetically modified commensal bacterium that can secrete Ang-(1-7) provides cardiopulmonary protection against PH. Thus, delivery of Ang-(1-7) by probiotic means could be considered an innovative therapeutic strategy for PH.
Abstract 014: Collecting Duct Specific Deletion of the (Pro)renin Receptor Modulates ENaC Expression
Authors: Ramkumar Nirupama , Stuart Deborah , Song Kai , Abraham Nikita , Wang Shuping , Ichihara Atsuhiro , Kohan Donald E
Published: June 2021

The renal tubular (pro)renin receptor (PRR) has been shown to modulate water balance, blood pressure and Na
+
homeostasis. We recently reported that
inducible
nephron wide deletion of the PRR results in Na
+
wasting, reduced epithelial Na
+
channel (ENaC) expression in the kidney and attenuated hypertensive response to angiotensin-II (Ang-II) infusion. In this study, we examined the effects of PRR deletion in collecting duct (CD) specific mouse models targeting either the principal cells (PC) or intercalated cells (IC). PC-specific PRR knockout (KO) mice were obtained by crossing floxed PRR mice with mice harboring AQP-2 Cre recombinase. Compared to floxed mice, PC specific KO PRR mice had no differences in PRR immunostaining but had 50% reduction in PRR mRNA in micro-dissected cortical CDs. No differences in blood pressure were observed between the two groups at baseline or following Ang-II infusion at 600 ng/kg/min. Similarly, plasma renin concentration and renal expression of ENaC protein isoforms were comparable between the two groups. To achieve IC-specific PRR deletion, floxed PRR mice were bred with mice expressing B-1 Cre recombinase. Compared to floxed controls, IC-specific PRR KO mice were smaller (KO body weight: 5.9 ± 1.3 g vs controls: 11.1± 1.2 g) and did not survive beyond 30 days after birth. IC-specific PRR KO mice also demonstrated marked reduction in renal medullary PRR immunostaining along with decreased renal expression of ENaC-α protein (50% reduction compared to controls), similar to the findings in nephron wide deletion of PRR. Taken together, these findings suggest that IC specific deletion of PRR but not PC-specific deletion modulates renal ENaC expression. Further studies evaluating ENaC activity in isolated cortical CDs from PC and IC specific PRR KO mice will help delineate the functional role of CD PRR in Na
+
homeostasis.
Abstract 024: PGC-1α is a Critical Activator of HO-1 That Protects Against Cardiomyopathy in Diabetic Mice Through Recruitment of Mitochondrial Fusion Proteins and Function
Authors: Cao Jian , McClung John A , Waldman Maayan , Singh Shailendra P , Schragenheim Joseph , Arad Michael , Hochhauser Edith , Abraham Nader
Published: June 2021

Introduction:
Diabetes mellitus type 2 (DM2) is associated with cardiovascular complications, which are characterized by increased oxidative stress (ROS) and inhibition of anti-oxidant genes such as heme oxygenase (HO-1), Super oxide dismutase (SOD2) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The latter that controls mitochondrial biogenesis, oxidative metabolism, and increased degradation of epoxyeicosatrienoic acids (EETs). Inhibition of these genes leads to increased myocardial stiffness and the development of cardiac hypertrophy and diastolic dysfunction.

Aim:
To assess whether PGC-1α plays a significant role in the development of diabetic cardiomyopathy in chronically obese mice.

Methods:
Leptin resistant (db/db) mice develop cardiomyopathy at the age of 5-6 month. Mice were treated with the EET agonist (EET-A) and with either lentivirus (Ln)- PGC-1α (Sh) or EET-A-Ln-PGC-1α scrambled for 3 additional months.

Results:
db mice exhibited impaired glucose tolerance, increased fasting blood glucose (366±21.9mg/dL vs.112±9.2 mg/dL, p<0.004), decreased oxygen consumption (VO
2
) (25.09±1.1ml/min vs. 55.37±5.92ml/min, p<0.002) and heart weight (0.17±0.02g vs.0.12±0.006g, p<0.05) compared to WT mice. EET agonists treatments improved fasting glucose levels (366±21.9mg/dL vs. 134±18.4 mg/dL, p<0.007) and oxygen consumption (25.09±1.1ml/min vs. 33.7±3.75ml/min, p<0.018), and reduced heart weight (0.17±0.02g vs.0.13±0.002g, p<0.0026). HO-1 levels were increased in cardiac tissue 22-fold (p<0.016). The beneficial effects of EET were reversed inhibition of PGC-1α in the EET-A-Ln PGC-1α (Sh) not in EET-A-Ln-PGC-1α scrambled group. The inhibition of PGC-1α (52% reduction, p<0.022) resulted in a reduction in the beneficial effects of EET-A as manifested by weight gain, the development of severe dilated cardiomyopathy and the attenuation of HO-1 and SOD2 (90% and 76% reduction respectively, p<0.02) and a decrease in mitochondrial fusion proteins Mfn1, 2 and OPa1.

Conclusion:
EET mediated restoration of mitochondrial function by PGC1α is essential for the enhancement of HO-1-myocyte contraction and the prevention of LV dysfunction in chronic obesity.
Abstract 028: Effects of N-acetyl-seryl-aspartyl-lysyl-proline on Inflammatory Cells During the Acute Stage of Myocardial Infarction
Authors: Nakagawa Pablo , Bordcoch de Martino Ginette , D’Ambrosio Martin , Jiang Xu , Carretero Oscar
Published: June 2021

Background:
The natural peptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) decreases inflammation in chronic diseases such as hypertension and heart failure. The effects of Ac-SDKP on acute inflammatory responses during myocardial infarction (MI) are unknown. During the first 72 hours post-MI, neutrophils, M1 macrophages (pro-inflammatory), and M2 macrophages (pro-resolution) and the release of myeloperoxidase (MPO) and matrix metalloproteinases (MMP) play a role in the development of cardiac rupture which is an uncommon, but fatal complication. We hypothesize that in the acute stage of MI, Ac-SDKP decreases the incidence of cardiac rupture and mortality by preventing the infiltration of immune cells and by decreasing the activation of MPO and MMP.

Methods:
MI was induced by the ligation of the left descending coronary artery in C57 mice. Vehicle or Ac-SDKP (1.6 mg/kg/d) was infused via osmotic minipump. Cardiac immune cell infiltration was assessed by flow cytometry, cardiac MPO and MMP activities were measured at 24-48 hrs post-MI. The incidence of cardiac rupture and mortality was determined at 7 days post-MI. Neutrophil migration was studied
in vitro
by chemotaxis transwell assay.

Results:
In infarcted mice, Ac-SDKP decreased the incidence of cardiac rupture from 51.0% (26 of 51 animals) to 27.3% (12/44; p=0.015) and mortality from 56.9% (29/51) to 31.8% (14/44; p=0.019). Ac-SDKP also reduced the cardiac infiltration by the M1 macrophages (veh: 1,495±236 vs Ac-SKDP: 765±69 cells/heart, p=0.027), without affecting M2 macrophages. Ac-SDKP did not affect neutrophil and MPO activity
in vivo
and neither affected neutrophil chemotaxis
in vitro
. However, Ac-SDKP prevented the activation of MMP-9 (veh: 3,686±508 vs Ac-SDKP: 1,696±512 optical density units, p=0.029) in infarcted hearts.

Conclusion:
Ac-SDKP prevents cardiac rupture and mortality in acute MI. These protective effects of Ac-SDKP are associated with a decrease in pro-inflammatory M1 macrophage infiltration and MMP-9 activation.

Perspective:
Cardiac rupture is an uncommon, but fatal complication of MI that could be prevented by the administration of Ac-SDKP or a peptidase resistant analog.
Abstract 032: Soluble fms-like Tyrosine Kinase-1 (sFlt-1)/Placental Growth Factor (PlGF) Imbalance Disrupts Vascular and Uteroplacental Gelatinolytic Matrix Metalloproteinase MMP-2 and -9 and Collagenolytic MMP-1 and -7 Balance in Hypertensive Pregnancy
Authors: Cui Ning , Ren ZongLi , Khalil Raouf A
Published: June 2021

Preeclampsia is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg) and fetal growth restriction. Placental ischemia could be an initiating event, but the linking mechanisms and tissue targets are unclear. Placental ischemia is associated with increased sFlt-1/PlGF ratio, and we have shown changes in MMPs in pregnant rat model of reduced uterine perfusion pressure (RUPP). To test the hypothesis that sFlt-1/PlGF imbalance could target vascular and uteroplacental MMPs, we tested if raising sFlt-1/PlGF ratio by infusing sFlt-1 (10 μg/kg/day) in Preg rats would increase BP and alter MMPs, and if correcting sFlt-1/PlGF ratio by infusing PlGF (20 μg/kg/day) in RUPP rats improves BP and reverses the changes in MMPs. On day 19, BP was recorded and the aorta, placenta, uterus and uterine artery were isolated for measuring MMP activity using gelatin and casein zymography and protein levels of MMPs and collagen I and IV using Western blots. BP was in Preg+sFlt 121±3 > Preg 93±7 and in RUPP+PlGF 97±4 < RUPP 118±4 mmHg. Litter size and pup weight were in Preg+sFlt < Preg and in RUPP+PlGF > RUPP. MMP-2 levels were in aorta of Preg+sFlt 3.30±0.05 < Preg 7.75±0.13, and in RUPP+PlGF 6.70±0.19 > RUPP 2.62±0.12. Similarly, MMP-2 in placenta, uterus and uterine artery and MMP-9 in all tissues were in Preg+sFlt < Preg and in RUPP+PlGF > RUPP. In contrast, MMP-1 levels were in aorta of Preg+sFlt 1.73±0.33 > Preg 0.55±0.49, and in RUPP+PlGF 0.53±0.18 < RUPP 4.04±0.30. Also, MMP-1 in placenta, uterus and uterine artery and MMP-7 in all tissues were in Preg+sFlt > Preg and in RUPP+PlGF < RUPP. The MMP-2 and -9 substrate collagen IV was in aorta of Preg+sFlt 0.16±0.00 > Preg 0.06±0.01, and in RUPP+PlGF 0.01±0.00 < RUPP 0.18±0.01. Similarly, collagen IV in placenta, uterus and uterine artery and the MMP-1 and -7 substrate collagen I in all tissues were in Preg+sFlt > Preg and in RUPP+PlGF < RUPP. Thus, sFlt-1/PlGF imbalance is a likely mechanism linking placental ischemia to decreased gelatinases, increased collagenases and improper vascular and uteroplacental remodeling. Correcting sFlt-1/PlGF balance by infusing PlGF could rectify the balance between gelatinolytic and collagenolytic MMPs and thereby restore proper vascular and uteroplacental remodeling in HTN-Preg.
Abstract 044: Deletion of Serum and Glucocorticoid-regulated Kinase 1 (SGK1) in T Cells Attenuates Hypertension and Renal/Vascular Dysfunction
Authors: Norlander Allison E , Saleh Mohamed A , Pandey Arvind K , Itani Hana A , Wu Jing , Xiao Liang , Dale Bethany L , Harrison David G , Madhur Meena S
Published: June 2021

We have previously shown that the T cell-derived pro-inflammatory cytokine, interleukin 17A (IL17A), is upregulated by and promotes angiotensin II (Ang II)-induced hypertension and contributes to renal and vascular dysfunction. It was recently demonstrated that an excess of 40 mM of sodium chloride enhances IL17A production from CD4+ T cells in an SGK1 dependent manner. Since dietary salt intake is associated with hypertension, we hypothesized that T cell SGK1 promotes hypertension and contributes to end-organ dysfunction. To test this hypothesis, we crossed SGK1
fl/fl
mice with
Tg
CD4cre
mice to delete SGK1 in T lymphocytes. Loss of T cell SGK1 resulted in a blunted blood pressure response following 2 weeks of Ang II infusion (24.8 mmHg reduction, p=0.01). Moreover, renal and vascular inflammation in response to Ang II infusion was abrogated in these mice compared to SGK1
fl/fl
control mice. Ang II infusion increased total (CD45+) leukocytes in the kidney from 55.4 to 120.4 x10
3
(p<0.01) in SGK1
fl/fl
mice while there was no increase in mice with T cell deletion of SGK1 (48.1 to 47.5x10
3
, p=ns). Similarly, Ang II increased total (CD45+) leukocytes in the aorta from 5.7 to 52.4x10
3
(p<0.01) in SGK1
fl/fl
mice compared to no increase in mice with T cell deletion of SGK1 (16.1 to 10.1x10
3
, p=ns). Furthermore, relaxation of mesenteric arterioles isolated from Ang II infused SGK1
fl/fl
mice in response to acetylcholine was impaired by 22.37% (p<0.0001) compared to a 2.62% (p=ns) impairment in vessels isolated from mice with T cell deletion of SGK1, demonstrating that the latter group has preserved endothelial function despite Ang II infusion. To assess renal dysfunction, we measured urinary albumin:creatinine ratio which increased 5.81-fold (p<0.01) in SGK1
fl/fl
mice infused with Ang II compared to 3.23-fold (p=ns) in mice without T cell SGK1, demonstrating that these mice are protected from Ang II-induced renal injury. Finally, we found that total numbers of splenic CD4+IL17A+ cells increase from 0.44% to 1.15% (p<0.05) in SGK1
fl/fl
mice infused with Ang II compared to no change (0.45% to 0.47%, p=ns) in mice without T cell SGK1. These studies demonstrate that T cell SGK1 may be a novel therapeutic target for hypertension and the associated end-organ dysfunction.
Abstract 077: Role of Suppressor of Cytokines Signaling 3 (SOCS3) in POMC Neurons in Regulating Metabolic and Cardiovascular Functions in Dietary-Induced Obesity
Authors: Wang Zhen , do Carmo Jussara , da Silva Alexandre , Aberdein Nicola , Hall John
Published: June 2021

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of leptin signaling, may contribute to the development of obesity-induced leptin resistance. Previously, we showed that activation of proopiomelanocortin (POMC) neurons mediates the chronic effects of leptin on blood pressure (BP) and glucose regulation. However, the role of SOCS3 in POMC neurons in regulating metabolic and cardiovascular functions in obesity is still unclear. To address this question, we used male and female mice with SOCS3 deleted only in POMC neurons (SOCS3
flox/flox
-POMC/cre) and flox control (SOCS3
flox/flox
) mice. After weaning, mice were fed normal chow until 20 wks of age; then glucose tolerance tests (GTT) were performed and telemetry probes were implanted to measure mean arterial pressure (MAP) 24-hrs/day. We found that at 23 wks of age, both male and female SOCS3
flox/flox
-POMC/cre mice weighed less than control mice (32±1 vs 37±2 g in male and 25±1 vs 27±1 g in female, n=9-11,
p
<0.05), but had similar daily food intake (3.5±0.2 g in male and 3.3±0.1 g in female) and MAP (114±1 vs 115±2 mmHg). Only male SOCS3
flox/flox
-POMC/cre mice exhibited improved glucose tolerance (AUC: 1059±52 vs 1283±54 mg/dL x 120 min, n=7-10,
p
<0.05) compared to controls. From 23 wks, mice were switched to a high fat diet (45%, HFD) for 6 wks. After HFD feeding, both male and female SOCS3
flox/flox
-POMC/cre mice had slightly reduced food intake (3.2±0.1 vs 3.5±0.2 g in male and 2.7±0.1 vs 3.0±0.2 g in female) and a trend toward lower body weight gain (10±1 vs 12±1 g in male and 4±1 vs 6±1 g in female), although the differences were not significant compared to controls. However, male and female SOCS3
flox/flox
-POMC/cre mice fed a HFD had significantly greater MAP increase (7±1 vs 1±1 mmHg, n=13-16,
p
<0.05) and an enhanced BP response to acute air-jet stress (AUC: 109±9 vs 74±12 mmHg x 5min, n=8-13,
p
<0.05). After HFD, glucose tolerance was impaired in all groups of mice compared to the baseline at 20 wks, but there were no differences between SOCS3
flox/flox
-POMC/cre and controls. These results suggest that deletion of SOCS3 in POMC neurons amplifies the BP response to a HFD and to acute stress, but has minimal effects on metabolic functions to HFD. (NHLBI PO1HL51971, NIGMS P20GM104357, AHA 14POST18160019)
Abstract 079: Hmox1 Activation Reprograms White Fat to Beige Adipose Tissue Through Recruitment of Cyp2C44-derived EET, pAMPK-PGC1α That Enhances Mitochondrial Mfn2 and Opa1
Authors: Abraham Nader G , Singh Shailendra P , Bellner Lars , Bamshad David , Drummond George
Published: June 2021

Introduction:
Hmox1

+/+

is critical in the regulation of insulin sensitivity and mitochondrial bioenergetics by regulating cellular heme-derived CO and bilirubin levels (Hosick and Stec 2015). We have demonstrated that high fat (HF) diets decreased HO-1 and PGC-1α. We examined the role of HO-1 on white and brown-fat like and energy expenditure genes.

Methods:
C57/B16 female mice, 5 wks old, were fed a HF diet for 24 wks. At 12 wks, when all mice had established pre-diabetic stage, cobalt protoporphyrin, (CoPP) was administered, i.p. (0.3 mg /100, BW), for the last 8 wks. Blood and fat tissues were collected, Cyp-2C44-derived EET, AMPK, HO-1, insulin receptors, and mito-fusion protein markers were determined in the three groups of mice: A) Control, B) HF, C) HF-CoPP. We generated adipoq-HO-1 knockout mouse model and mRNA and protein signaling, adiposity, oxygen consumption were determined and compared to adipocyte culture depressed in HO.

Result:
CoPP increased HO-1 expression by 20-fold (p<0.02), EETs (p<0.05), PGC-1α (p<0.05), pAMPK (p<0.05) and Mfn1/2 (p<0.05), Opa1 and OXPHOS (p<0.05), oxygen consumption (Vo
2
), but decreased fasting glucose levels. These was associated with a decreases in VAT, SAT (p<0.02). Adipoq-HO-1
-/-
female mice exhibit marked decrease in pAMPK, Cyp2C44, PGC1α, Mfn1/2, Opa1, UCP1 and SIRT1 but increased adipogenic markers including Mest/Peg1 in adipose tissues.

Conclusion:
Overexpression of HO-1-derived CO and bilirubin enhances UCP1, Cyp2C44, pAMPK-PGC1α to turn on a robust program of energy expenditure genes and reprogrammed white (VAT, SAT) to beige adipose and brown-like adipocytes. Deletion of HO-1 or suppression of HO-1 led to metabolic dysfunction, hyperglycemia as in white fat to exhibit significant low energy expenditure, OXPHOS and VO
2
.

Mechanistically, absence of HO-1 decreased AMPK signaling; thereby disrupting EET-PGC-1α expression and mitochondrial oxidative metabolism. These findings offer new insight for the development of obesity treatment strategies through restoration of HO-1 and adipocyte function.
Abstract 088: Chronic Efferent Vagal Stimulation Enhances Norepinephrine-mediated Inhibition of Splenic Pro-inflammatory Cytokine Release in Lupus Hypertension
Authors: Pham Grace S , Fairley Amber S , Mathis Keisa W
Published: June 2021

Hypertension is prevalent in the autoimmune disease systemic lupus erythematosus (SLE), occurring with alarming frequency in reproductive-age women. Recent studies implicate the adaptive immune system in the development and maintenance of hypertension, and neuroimmune pathways may regulate this source of inflammation. One example is the cholinergic anti-inflammatory pathway (CAP), an endogenous nerve-to-spleen mechanism that regulates splenic pro-inflammatory cytokine release. We hypothesized that this pathway is impaired in SLE and that chronic stimulation of the CAP at the level of the efferent vagus nerve would attenuate hypertension in SLE. Starting at 30 and 32 weeks of age, female
NZBWF1
SLE mice and
NZW
control mice were treated with the pharmacologic efferent vagal stimulators CNI-1493 (CNI; 8mg/kg; twice weekly; i.p.) or galantamine (GAL; 4mg/kg; daily; i.p.), or saline. At 34 weeks of age, we measured mean arterial pressure (MAP), finding that MAP (mmHg) in SLE mice was elevated compared to controls (139.83 ± 4.56 vs. 120.70 ± 2.96; n=4-6/group, p = 0.002), while the rise in MAP was prevented by CNI (134.45 ± 3.07)and GAL (129.25 ± 3.97) in SLE mice. We further hypothesized that splenocytes isolated from SLE mice conditioned by efferent vagal stimulation would release fewer pro-inflammatory cytokines in the presence of norepinephrine, which stimulates splenic β2 adrenergic receptors. We incubated isolated splenocytes for 24 hours at 37°C with and without norepinephrine (100 μM), then measured pro-inflammatory cytokines in the supernatant via ELISA. Compared to control mice, splenocytes from SLE mice secreted 70.7% and 146.5% higher concentrations of IL-6 and TNF-α (8.24 vs. 4.83 and 2.79 vs. 1.13 pg/mL, respectively; n=2/group) in the presence of norepinephrine. Compared to saline-treated SLE mice, splenocytes from CNI and GAL-treated SLE mice released fewer cytokines when incubated with norepinephrine (8.24 vs. 5.31 and 5.79 pg/mL IL-6; 2.79 vs. 2.18 and 0.81 pg/mL TNF-α; n=2/group). These
in vivo
and
in vitro
data suggest that stimulation of the CAP at the level of the efferent vagus may promote anti-inflammatory splenocyte activity, which may be protective against hypertension in the setting of chronic inflammation.
Abstract 099: Functional Remodeling of the Renal Vasculature Precedes the Establishment of Salt-sensitive Hypertension in Eln-deficient Mice
Authors: Owens Elizabeth A , Jie Li , Reyes Beverly , Van Bockstaele Elisabeth J , Osei-Owusu Patrick
Published: June 2021

Vascular stiffening due to elastin deficiency is a leading risk for hypertension and chronic kidney disease (CKD). However, the mechanisms by which elastin deficiency is involved in the pathogenesis of hypertension and/or CKD are poorly understood. Here, we used elastin heterozygous mice (
Eln+/-
), an animal model of elastin insufficiency, to test the hypothesis that renal dysfunction due to elastin deficiency occurs independently of and precedes the development of hypertension in this mouse model.

We assessed blood pressure (BP) and renal hemodynamics in 30-day (P30) and 12-week old anesthetized male and female mice. At P30, mean blood pressure of
Eln+/-
was similar to wild type (WT) controls (
Eln+/-
, 79 ± 5 vs. WT, 69±3 mmHg,
P
= 0.06); however, renal blood flow was lower (
Eln+/-
2.9 ± 0.2 vs. WT 4.0 ± 0.5 mL/min/g KW,
P
= 0.03) whereas renal vascular resistance (RVR;
Eln+/-
29 ± 3 vs. WT 18 ± 3 mmHg/mL/min/g KW, P = 0.03) was augmented at baseline in
Eln+/-
mice. At 12 wks old, RVR remained elevated while filtration fraction was higher in male
Eln+/-
relative to WT mice (
Eln+/-
44 ± 3 vs. WT 38±5 %
P
= 0.07).
Eln+/-
mice showed isolated systolic hypertension that was evident only at nighttime (
Eln+/-
136 ± 2 vs. WT 112 ± 6 mmHg,
P
<0.01). Acute salt loading with 6% dietary sodium increased daytime systolic blood pressure only in male
Eln+/-
mice (
Eln+/-
118 ± 5 vs. WT 102 ± 6 mmHg,
P
= 0.03), causing a rightward shift and blunted slope of the pressure-natriuresis curve. Renal interlobar artery basal tone and myogenic response to increasing intraluminal pressure at P10 were similar (
Eln+/-
78 ± 3 vs. WT 67 ± 6 %
P
= 0.06) whereas they were augmented at P30 (
Eln+/-
63 ± 4 vs. WT 49 ± 6 %
P
= 0.05) and at 12 wks old in
Eln+/-
mice (
Eln+/-
50 ± 2 vs. WT 33 ± 3 %
P
< 0.01), and normalized by the AT1R blocker, candesartan (
Eln+/-
22 ± 9 vs. WT 8 ± 5 %
P
= 0.10).

We conclude that AT1R mediates augmented mechanotransduction and renal vascular dysfunction due to
Eln
insufficiency that in turn contribute to altered renal sodium handling and increased BP. Such prolonged systemic BP elevation leads to glomerular structural damage due to high renal perfusion pressure. Therefore, therapies that target the AT1R to control BP in patients with elastin deficiency may be beneficial in preventing hypertension-evoked kidney damage.
Abstract 102: Role of Renal Tubular NHE3 for Blood Pressure and Salt Homeostasis
Authors: Rieg Timo , Poulsen Soren B , Dominguez Rieg Jessica A , Fenton Robert A
Published: June 2021

The Na
+
/H
+
exchanger isoform 3 (NHE3) is expressed in the intestine and the kidney where it facilitates Na
+
absorption and H
+
secretion. The importance of NHE3 in the kidney for NaCl homeostasis and blood pressure regulation, relative to the intestine, is not known. To investigate this, we examined kidney-specific NHE3 knockout mice (NHE3
loxloxPax8Cre
) and control mice (Con, NHE3
loxlox
) under normal, low or high dietary NaCl intake. Under normal dietary NaCl intake, no significant differences were detected between genotypes in body weight, fluid or food intake, blood pH and plasma Na
+
, K
+
or aldosterone levels. However, urinary pH was significantly elevated in NHE3
loxloxPax8Cre
mice and GFR was significantly lower (457±20 vs 358±17 μl/min, P<0.05). High NaCl intake (4% for 10 days) had no impact on plasma Na
+
in Con mice; but plasma Na
+
concentrations in NHE3
loxloxPax8Cre
mice were susceptible to the effects of low NaCl (<0.01% for 10 days) (-3.9±1.0 mM, P<0.05) or high NaCl intake (+2.2±0.6 mM, P<0.05) compared to baseline conditions. Low NaCl diet decreased plasma K
+
levels in Con mice (-0.5±0.2 mM, P<0.05) but to a significantly greater amount in NHE3
loxloxPax8Cre
mice (-1.2±0.1 mM, P<0.05). Plasma aldosterone was not significantly different between Con and NHE3
loxloxPax8Cre
mice under low (345±96 vs 498±78 pg/ml) or high NaCl intake (60±19 vs 86±20 pg/ml). Low NaCl intake decreased GFR in Con (-110±13 μl/min, P<0.05) and NHE3
loxloxPax8Cre
(-99±8 μl/min, P<0.05) mice, whereas high NaCl intake was without effect on GFR in either genotype. Dietary NaCl did not affect blood pressure in Con mice (low NaCl: 102±3; high NaCl: 102±3 mmHg); however, blood pressure was significantly lower in NHE3
loxloxPax8Cre
mice and salt-sensitive (low NaCl: 81±2; high NaCl: 91±2 mmHg, P<0.05). Alterations in the abundances of several Na
+
transport proteins within the kidney tubule system were also apparent in NHE3
loxloxCre
mice under different dietary conditions. In conclusion, renal NHE3 is required to maintain blood pressure and steady state plasma Na
+
levels when dietary NaCl intake is modified.