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The current novel coronavirus disease 2019 (COVID-19) pandemic is revealing profound differences between men and women in disease outcomes worldwide. In the United States, there has been inconsistent reporting and analyses of male-female differences in COVID-19 cases, hospitalizations, and deaths. We seek to raise awareness about the male-biased severe outcomes from COVID-19, highlighting the mechanistic differences including in the expression and activity of angiotensin-converting enzyme 2 (ACE2) as well as in antiviral immunity. We also highlight how sex differences in comorbidities, which can be associated with both age and race, impact male-biased outcomes from COVID-19.

Concerns regarding sex differences are increasingly pertinent in scientific and societal arenas. Although biological sex and socio-cultural gender are increasingly recognized as important modulators of renal function under physiological and pathophysiological conditions, gaps remain in our understanding of the mechanisms underlying sex differences in renal pathophysiology, disease development, progression and management. In this Perspectives article, we discuss specific opportunities for future research aimed at addressing these knowledge gaps. Such opportunities include the development of standardized core data elements and outcomes related to sex for use in clinical studies to establish a connection between sex hormones and renal disease development or progression, development of a knowledge portal to promote fundamental understanding of physiological differences between male and female kidneys in animal models and in humans, and the creation of new or the development of existing resources and datasets to make them more readily available for interrogation of sex differences. These ideas are intended to stimulate thought and interest among the renal research community as they consider sex as a biological variable in future research projects.

OBJECTIVES/GOALS: Approximately 37 million people in the U.S. have chronic kidney disease, which is a major risk factor for cardiovascular and end stage renal diseases. PPAR-αknockout (KO) mice exhibit increased renal inflammation and blood pressure. In this study, we investigated the role of PPAR-αin renal function in a mouse model of hypertension. METHODS/STUDY POPULATION: Male 4-month-old wild type (WT) and PPAR-αKO mice were instrumented with radio transmitters by artery canulation (Data Science Intl). This method minimizes stress and artifacts by avoiding the use of tethering, restraining, or anesthetizing the mice during data sampling. After recovery from surgery, we continuously measured mean arterial pressure (MAP) via radio telemetry in conscious ambulatory mice. After baseline MAP was established, vehicle (Veh; saline) or angiotensin II (Ang II) were infused using an osmotic minipump at a slow pressor dose (400 ng/kg/min) for 12 days. On day 12, we injected an intravenous bolus of fluorescin-sinistrin (3.74µl/g body weight) and collected 8 blood samples (20µl/sample) over 75 minutes to enable calculation of the glomerular filtration rate (GFR) using [GFR = I/(A/α+ B/ß)]. RESULTS/ANTICIPATED RESULTS: Similar to our prior observations, no significant (ns) differences in baseline MAP were observed between WT and PPAR-αKO mice [(mmHg): WT (n=6), 111 ± 20 vs. PPAR-αKO (n=6), 113 ± 10; ns] whereas after 12 days of the slow pressor effect of Ang II, MAP was increased in both strains [(mmHg): WT (n=8), 138 ± 11# vs. PPAR-αKO (n=8) , 156 ± 16#; #p DISCUSSION/SIGNIFICANCE: PPAR-αprotects mice from worsening hypertension and is critical to preserving GFR during normotensive conditions. Ongoing studies are further investigating how PPAR-αregulates renal function. These finding suggest therapeutics designed to increase PPAR-αactivity could have clinical benefit in chronic kidney disease.

There is a growing appreciation by the biomedical community that studying the impact of sex and gender on health, aging, and disease will lead to improvements in human health. Sex- and gender-based comparisons can inform research on disease mechanisms and the development of new therapeutics as well as enhance scientific rigor and reproducibility. This review will assist basic researchers, clinical investigators, as well as epidemiologists, population, and social scientists by providing an annotated bibliography of currently available resource tools on how to consider sex and gender as independent variables in research design and methodology. These resources will assist investigators applying for funding from the National Institutes of Health since all grant applicants will be required (as of January 25, 2016) to address the role of sex as a biological variable in vertebrate animal and human studies.

Background Biological sex is a critical determinant in cardiovascular and renal disease outcomes. Although angiotensin II (Ang II) infusion is widely used to model hypertension in mice and rats, little is known about its effects in the Syrian hamster, a small rodent increasingly used for translational research. This study aimed to develop a model of chronic Ang II-induced hypertension in Syrian hamsters and investigate sex-specific differences in blood pressure, renal pathology, and components of the renin-angiotensin system (RAS). Methods Male and female Syrian hamsters (8–9 weeks old) were infused subcutaneously with Ang II (200 ng/kg/min) or saline via osmotic minipumps for four weeks. Mean arterial pressure (MAP) and kidney wet weight were determined on the euthanasia day. The kidneys were analyzed for renal pathology; renal RAS enzymes (ACE and ACE2) were measured by colorimetric assay and qPCR; cytokines (IL-6 and IL-1β) were measured by qPCR; and the angiotensin receptor type 1 (AT1R) was measured by radioligand binding and qPCR. Results Ang II infusion increased MAP in both sexes but elicited a significantly greater response in females (+ 50 mmHg) than males (+ 27 mmHg, p  < 0.005). Female hamsters exhibited pronounced kidney injury, including acute tubular necrosis, glomerular sclerosis, and vascular fibrinoid necrosis, along with a 2-fold increase in kidney weight normalized to body weight. Ang II significantly downregulated renal ACE, ACE2, and AT 1 R expression and activity in females but not in males. Renal IL-6 and IL-1β mRNA levels were elevated 20-fold and 3.9-fold, respectively, in females, compared to modest increases in males. Conclusions Female Syrian hamsters exhibit heightened vulnerability to Ang II-induced hypertension and renal damage compared to males, marked by exaggerated blood pressure elevation, enhanced renal inflammation, and suppression of classical RAS components. This novel hamster model provides a unique platform for studying sex-specific mechanisms of hypertension and renal pathology, with translational relevance for subpopulations of women who are at increased risk of Ang II-dependent hypertension-associated renal disease. Plain english summary High blood pressure (also known as hypertension) is a major risk factor for heart and kidney disease. Men and women often experience these conditions differently, but scientists still don’t fully understand why. In this study, researchers focused on how male and female Syrian hamsters respond to a substance called angiotensin II, which is known to raise blood pressure and is commonly used in research to mimic high blood pressure in animals. Over four weeks, male and female hamsters were given either angiotensin II or a harmless salt solution. The researchers measured blood pressure and looked at changes in kidney health and in a system of hormones that helps control blood pressure, called the renin-angiotensin system. They found that angiotensin II caused a much bigger rise in blood pressure in female hamsters than in males. The female hamsters also showed more severe kidney damage, including scarring and inflammation. Important hormones and enzymes that usually help regulate blood pressure were found to be lower in females after treatment, while markers of inflammation were much higher. These results suggest that female hamsters are more sensitive to angiotensin II and may be more at risk of developing severe kidney problems from high blood pressure. This new hamster model offers a valuable way to study how men and women differ in their response to high blood pressure and could help researchers find better, more personalized treatments—especially for women who may be more vulnerable to certain types of hypertension-related kidney disease. Highlights Developed a novel model of angiotensin II-induced hypertension in Syrian hamsters. Female hamsters showed significantly higher increases in blood pressure than males in response to angiotensin II. Females exhibited more severe kidney damage, including tubular necrosis, glomerular sclerosis, and vascular injury. Only in females, angiotensin II reduced key components of the renal renin-angiotensin system (ACE, ACE2, AT1R). Inflammatory markers (IL-6, IL-1β) were dramatically elevated in female kidneys compared to males.

OBJECTIVES/GOALS: In the U.S., over 4 million people including children experience transient periods of undernutrition annually. Cardio-metabolic and renal diseases are more prevalent in this population. We are investigating therapeutic strategies to reverse the long-term risk of these diseases in a rat model of transient undernutrition followed by refeeding. METHODS/STUDY POPULATION: Thirty six female Fischer rats (3-months of age) were initially divided into 2 groups. Half were fed regular chow (CT) while the other half were severely food restricted (sFR) by 60% from 0-2 weeks (wks) followed by refeeding from 2-14 wks (sFR-Refed). These 2 groups were then subdivided and treated ± metformin (Met) from wk 7 to wk 12 (n=9/group). High precision ultrasound was conducted on live rats to assess heart and kidney function immediately after the sFR period ended (wk 2) and at the end of the study (wk 14). At the conclusion of the experiment, the rats were sacrificed and the histology of the kidney and heart tissues were analyzed in hematoxylin and eosin-stained sections. The protein to DNA ratio was also calculated in homogenates from these tissues. RESULTS/ANTICIPATED RESULTS: In sFR-Refed rats, cardiac output (CO), heart rate (HR) and renal artery blood flow (RBF) were decreased by 11 ± 1.5%#, 7.0 ± 6.0% and 22 ± 0.6%#, respectively, compared to control (CT) rats; #p<0.05. Mean glomerular diameter was reduced in the kidneys of sFR-refed rats compared to CT and this effect was attenuated by metformin treatment [(µm): CT, 406 ± 31; sFR-Refed, 383 ± 11, p<0.06; CT+Met, 393 ± 18; sFR-Refed+Met, 407 ± 18*]. Furthermore, the mean cardiomyocyte thickness was reduced in sFR-Refed rats compared to controls while metformin treatment prevented this effect [(µm): CT, 16.4 ± 3.6; sFR-Refed, 11.5 ± 2.3#; CT+Met, 16.4 ± 3.6; sFR-Refed+Met, 15.9 ± 3.2*]. #p<0.05 vs. CT, same treatment; *p<0.05 vs. Met, same diet; two-way ANOVA. DISCUSSION/SIGNIFICANCE: These findings have promising implications for metformin use to mitigate long-term impairments in heart and kidney structure and function in individuals who have experienced bouts of undernutrition earlier in life for either voluntarily (e.g., very low calorie dieting) or involuntary (e.g., very low food security) reasons.

Severe food restriction (FR) is associated with blood pressure (BP) and cardiovascular dysfunction. The renin-angiotensin system (RAS) regulates BP and its dysregulation contributes to impaired cardiovascular function. Female Fischer rats were maintained on a control (CT) or severe FR (40% of CT) diet for 14 days. In response to severe FR, BP allostasis was achieved by up-regulating circulating Ang-[1–8] by 1.3-fold through increased angiotensin converting enzyme (ACE) activity and by increasing the expression of AT 1 Rs 1.7-fold in mesenteric vessels. Activation of the RAS countered the depressor effect of the severe plasma volume reduction (≥30%). The RAS, however, still underperformed as evidenced by reduced pressor responses to Ang-[1–8] even though AT 1 Rs were still responsive to the depressor effects of an AT 1 R antagonist. The aldosterone (ALDO) response was also inadequate as no changes in plasma ALDO were observed after the large fall in plasma volume. These findings have implications for individuals who have experienced a period(s) of severe FR (e.g., anorexia nervosa, dieters, natural disasters) and suggests increased activity of the RAS in order to achieve allostasis contributes to the cardiovascular dysfunction associated with inadequate food intake.

A national survey characterized training and career development for translational researchers through Clinical and Translational Science Award (CTSA) T32/TL1 programs. This report summarizes program goals, trainee characteristics, and mentorship practices. A web link to a voluntary survey was emailed to 51 active TL1 program directors and administrators. Descriptive analyses were performed on aggregate data. Qualitative data analysis used open coding of text followed by an axial coding strategy based on the grounded theory approach. Fifty out of 51 (98%) invited CTSA hubs responded. Training program goals were aligned with the CTSA mission. The trainee population consisted of predoctoral students (50%), postdoctoral fellows (30%), and health professional students in short-term (11%) or year-out (9%) research training. Forty percent of TL1 programs support both predoctoral and postdoctoral trainees. Trainees are diverse by academic affiliation, mostly from medicine, engineering, public health, non-health sciences, pharmacy, and nursing. Mentor training is offered by most programs, but mandatory at less than one-third of them. Most mentoring teams consist of two or more mentors. CTSA TL1 programs are distinct from other NIH-funded training programs in their focus on clinical and translational research, cross-disciplinary approaches, emphasis on team science, and integration of multiple trainee types. Trainees in nearly all TL1 programs were engaged in all phases of translational research (preclinical, clinical, implementation, public health), suggesting that the CTSA TL1 program is meeting the mandate of NCATS to provide training to develop the clinical and translational research workforce.

OBJECTIVES/GOALS: Hypertension is a major risk factor for coronavirus disease 2019 (COVID-19) severity. Our goal was to determine if hypertension worsens lung pathology induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters. METHODS/STUDY POPULATION: Male hamsters (7-8 weeks old) were infused with angiotensin II (AII; 200 ng/kg/min via osmotic minipump) for 4 weeks to induce hypertension. During the last week of the infusion, the hamsters were inoculated intranasally with vehicle (V) or SARS-CoV-2 (S; 1 x 105 plaque forming units/ml). Half of the hamsters were sacrificed 1 day post-inoculation (dpi-1) and the other half on dpi-6. Two scoring systems were applied to lung tissue sections stained with hematoxylin and eosin to determine the degree and severity of lung pathology: the first system assessed all pertinent alterations in the lungs, while the second system only assessed the pathology related to the pulmonary vasculature. Lung histopathology scores were calculated as the sum of the airway and lung alveolar scores in arbitrary units (AU). RESULTS/ANTICIPATED RESULTS: Studies revealed that the SARS-CoV-2-infected hamsters exhibited a 76-fold higher total airway score compared to vehicle controls [(AU): V, 0.25 ± 0.1; S, 19.00 ±1.35; p<0.05; n=4]. Total lung alveolar scores (27-fold) [(AU): V, 0.30 ± 0.11; S, 8.0 ± 4.1; p<0.05; n=4] and total vascular scores (17-fold) [(AU): V, 0.35 ± 0.2; S, 6.0 ±1.4; p<0.05; n=4] were also markedly higher compared to controls on dpi-1. AII increased blood pressure, which was sustained through the 4-week infusion period. Under these conditions, body weight slightly dropped by 4.5%. Ongoing studies are assessing the effect of hypertension on the % of airway, alveoli and vessels affected, airway and alveolar severity, and bronchiolar epithelial and type II pneumocyte hyperplasia. DISCUSSION/SIGNIFICANCE: Establishing the hypertensive hamster as a small animal model of COVID-19 will facilitate investigations into why preexisting hypertension is a risk factor for disease severity. These studies could lead to the development of novel therapeuticsfor treating COVID-19 patients with hypertension.

Background Many studies have shown malnutrition and inadequate caloric consumption have adverse acute effects on cardiovascular structure and function. Methods To determine the adverse long term cardiovascular effects, we studied cardiac morphology and function in female (F) and male (M) severe food restricted rats 3 months after refeeding (sFR-Refed). Results Two weeks of a normal chow diet in which calories were reduced by 60% decreased body weight (BW) by approximately 15% in both sexes. Within 2 weeks of refeeding, no differences in BW were detected between CT and sFR-Refed groups. However, male rats gained almost 3 times more BW than the females over the 3-month refeeding period. Sex differences were also observed in cardiac pathology. Hearts from F-sFR-Refed rats exhibited more atrophy and less hypertrophy, while M-sFR-Refed rats predominantly exhibited hypertrophic remodeling. While there were no differences in the frequency of ventricular arrhythmias induced by ischemia/reperfusion (I/R) in the isolated heart between M-CT and M-sFR-Refed rats, I/R induced twice as many arrhythmias in the F-sFR-Refed rats compared to F-CT. Conclusions These findings indicate the female heart is more susceptible to the long term adverse cardiovascular effects of sFR months after refeeding. Thus, this study provides a rationale for studying sex differences in cardiovascular risk in individuals who experience sFR for voluntary (e.g., very low-calorie dieting) or involuntary (e.g., poverty) reasons earlier in life. Highlights What are the long-term effects of a 2-week period of severe food restriction (sFR) on cardiac structure and function months after refeeding (sFR-Refed) in male and female rats? This study shows sex differences exist in cardiac pathology months after refeeding. A majority of cardiomyocytes were atrophied in F-sFR-Refed rats, while in M-sFR-Refed rats, the cardiomyocytes predominantly exhibited hypertrophic remodeling. While there were no differences in the frequency of ventricular arrhythmias induced by ischemia/reperfusion (I/R) in the isolated heart between M-CT and M-sFR-Refed rats, I/R induced twice as many arrhythmias in the F-sFR-Refed rats compared to the controls. Our findings have implications for the long-term risk of developing cardiovascular disease in individuals who have voluntarily or involuntarily experienced periods of sFR earlier in their lives, and that woman may be at greater cardiovascular risk than men.