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      Sex and gender differences in hypertensive kidney injury

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      American Journal of Physiology-Renal Physiology
      American Physiological Society

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          Abstract

          <p class="first" id="d4337471e141">Hypertension is a complex, multifaceted disorder, affecting ~1 in 3 adults in the United States. Although hypertension occurs in both men and women, there are distinct sex differences in the way in which they develop hypertension, with women having a lower incidence of hypertension until the sixth decade of life. Despite observed sex differences in hypertension, little is known about the molecular mechanisms underlying the development of hypertension in females, primarily because of their underrepresentation in both clinical and experimental animal studies. The first goal of this review is to provide a concise overview of the participation of women in clinical trials, including a discussion of the importance of including females in basic science research, as recently mandated by the National Institutes of Health. The remaining portion of the review is dedicated to identifying clinical and experimental animal studies that concentrate on gender and sex differences in hypertensive kidney disease, ending with a proposed role for T cells in mediating sex differences in blood pressure. </p>

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          Most cited references64

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          T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury.

          Angiotensin (Ang) II induces hypertension by mechanisms mediated in part by adaptive immunity and T effector lymphocytes. T regulatory lymphocytes (Tregs) suppress T effector lymphocytes. We questioned whether Treg adoptive transfer would blunt Ang II-induced hypertension and vascular injury. Ten- to 12-week-old male C57BL/6 mice were injected IV with 3 ×10(5) Treg (CD4(+)CD25(+)) or T effector (CD4(+)CD25(-)) cells, 3 times at 2-week intervals, and then infused or not with Ang II (1 μg/kg per minute, SC) for 14 days. Ang II increased systolic blood pressure by 43 mm Hg (P<0.05), NADPH oxidase activity 1.5-fold in aorta and 1.8-fold in the heart (P<0.05), impaired acetylcholine vasodilatory responses by 70% compared with control (P<0.05), and increased vascular stiffness (P<0.001), mesenteric artery vascular cell adhesion molecule expression (2-fold; P<0.05), and aortic macrophage and T-cell infiltration (P<0.001). All of the above were prevented by Treg but not T effector adoptive transfer. Ang II caused a 43% decrease in Foxp3(+) cells in the renal cortex, whereas Treg adoptive transfer increased Foxp3(+) cells 2-fold compared with control. Thus, Tregs suppress Ang II-mediated vascular injury in part through anti-inflammatory actions. Immune mechanisms modulate Ang II-induced blood pressure elevation, vascular oxidative stress, inflammation, and endothelial dysfunction.
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            Potential Role of Regulatory T Cells in Reversing Obesity-Linked Insulin Resistance and Diabetic Nephropathy

            OBJECTIVE To assess the potential role of FoxP3-expressing regulatory T cells (Tregs) in reversing obesity-linked insulin resistance and diabetic nephropathy in rodent models and humans. RESEARCH DESIGN AND METHODS To characterize the role of Tregs in insulin resistance, human visceral adipose tissue was first evaluated for Treg infiltration and second, the db/db mouse model was evaluated. RESULTS Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects. To further evaluate the pathogenic role of Tregs in insulin resistance, the db/db mouse model was used. Treg depletion using an anti-CD25 monoclonal antibody enhanced insulin resistance as shown by increased fasting blood glucose levels as well as an impaired insulin sensitivity. Moreover, Treg-depleted db/db mice developed increased signs of diabetic nephropathy, such as albuminuria and glomerular hyperfiltration. This was paralleled by a proinflammatory milieu in both murine visceral adipose tissue and the kidney. Conversely, adoptive transfer of CD4+FoxP3+ Tregs significantly improved insulin sensitivity and diabetic nephropathy. Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8+CD69+ T cells in visceral adipose tissue and kidneys of Treg-treated animals. CONCLUSIONS Data suggest a potential therapeutic value of Tregs to improve insulin resistance and end organ damage in type 2 diabetes by limiting the proinflammatory milieu.
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              Representation of women in randomized clinical trials of cardiovascular disease prevention.

              The 2007 American Heart Association guidelines for cardiovascular disease prevention in women drew heavily on results from randomized clinical trials; however, representation of women in trials of cardiovascular disease prevention has not been systematically assessed. We abstracted 156 randomized clinical trials cited by the 2007 women's prevention guidelines to determine female representation over time and by clinical indication, prevention type, location of trial conduct, and funding source. Both women and men were represented in 135 of 156 (86.5%) trials; 20 trials enrolled only men; 1 enrolled only women. Among all trials, the proportion of women increased significantly over time, from 9% in 1970 to 41% in 2006. Considering only trials that enrolled both women and men, female enrollment was 18% in 1970 and increased to 34% in 2006. Female representation was higher in international versus United States-only trials (32.7% versus 26.7%) and primary versus secondary prevention trials (42.6% versus 26.6%). Female enrollment was comparable in government/foundation-funded versus industry-funded trials (31.9% versus 31.5%). Representation of women was highest among trials in hypertension (44%), diabetes (40%), and stroke (38%) and lowest for heart failure (29%), coronary artery disease (25%), and hyperlipidemia (28%). By contrast, women accounted for 53% of all individuals with hypertension, 50% with diabetes, 51% with heart failure, 49% with hyperlipidemia, and 46% with coronary artery disease. Sex-specific results were discussed in only 31% of primary trial publications. Enrollment of women in randomized clinical trials has increased over time but remains low relative to their overall representation in disease populations. Efforts are needed to reach a level of representation that is adequate to ensure evidence-based sex-specific recommendations.
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                Author and article information

                Journal
                American Journal of Physiology-Renal Physiology
                American Journal of Physiology-Renal Physiology
                American Physiological Society
                1931-857X
                1522-1466
                October 2017
                October 2017
                : 313
                : 4
                : F1009-F1017
                Article
                10.1152/ajprenal.00206.2017
                5668592
                28724606
                6ff9ad4e-0251-426a-89d6-948e4b92f68e
                © 2017
                History

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