There is extensive evidence that activation of the immune system is both necessary and required for the development of Ang II-induced hypertension in males. The purpose of this study was to determine if sex differences exist in the ability of the adaptive immune system to induce Ang II-dependent hypertension and whether central and renal T cell infiltration during Ang II-induced hypertension is sex-dependent. Rag-1−/− mice, lacking both T and B cells, were used. Male and female Rag-1−/− mice received adoptive transfer of male CD3+ T cells 3 weeks prior to 14 day Ang II infusion (490ng/kg/min). Blood pressure was monitored via tail cuff. In the absence of T cells, systolic blood pressure (SBP) responses to Ang II were similar between sexes (Δ22.1mmHg males vs. Δ18mmHg females). After adoptive transfer of male T cells, Ang II significantly increased SBP in males (Δ37.7mmHg, p<0.05) compared to females (Δ13.7mmHg). Flow cytometric analysis of total T cells and CD4+, CD8+, and regulatory Foxp3+-CD4+ T cell subsets identified that renal lymphocyte infiltration was significantly increased in males vs females in both control and Ang II infused animals (p<0.05). Immunohistochemical staining for CD3+ positive T cells in the SFO region of the brain was increased in males compared to females. These results suggest that female Rag-1−/− mice are protected from male T cell-mediated increases in Ang II-induced hypertension as compared to their male counterparts, and this protection may involve sex differences in the magnitude of T cell infiltration of the kidney and brain.

Romero-Aleshire MJ, Diamond-Stanic MK, Hasty AH, Hoyer PB, Brooks HL. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 297: R587-R592, 2009. First published May 13, 2009 doi:10.1152/ajpregu.90762.2008.-Factors comprising the metabolic syndrome occur with increased incidence in postmenopausal women. To investigate the effects of ovarian failure on the progression of the metabolic syndrome, female B 6C3F1 mice were treated with 4-vinylcyclohexene diepoxide (VCD) and fed a high-fat (HF) diet for 16 wk. VCD destroys preantral follicles, causing early ovarian failure and is a well-characterized model for the gradual onset of menopause. After 12 wk on a HF diet, VCD-treated mice had developed an impaired glucose tolerance, whereas cycling controls were unaffected [12 wk AUC HF mice 13,455 Ϯ 643 vs. HF/VCD 17,378 Ϯ 1140 mg/dl/min, P Ͻ 0.05]. After 16 wk on a HF diet, VCD-treated mice had significantly higher fasting insulin levels (HF 5.4 Ϯ 1.3 vs. HF/VCD 10.1 Ϯ 1.4 ng/ml, P Ͻ 0.05) and were significantly more insulin resistant (HOMA-IR) than cycling controls on a HF diet (HF 56.2 Ϯ 16.7 vs. HF/VCD 113.1 Ϯ 19.6 mg/dl ⅐ U/ml, P Ͻ 0.05). All mice on a HF diet gained more weight than mice on a standard diet, and weight gain in HF/VCD mice was significantly increased compared with HF cycling controls. Interestingly, even without a HF diet, progression into VCD-induced menopause caused a significant increase in cholesterol and free fatty acids. Furthermore, in mice fed a standard diet (6% fat), insulin resistance developed 4 mo after VCD-induced ovarian failure. Insulin resistance following ovarian failure (menopause) was prevented by estrogen replacement. Studies here demonstrate that ovarian failure (menopause) accelerates progression into the metabolic syndrome and that estrogen replacement prevents the onset of insulin resistance in VCD-treated mice. Thus, the VCD model of menopause provides a physiologically relevant means of studying how sex hormones influence the progression of the metabolic syndrome.estrogen; cholesterol; glucose; insulin BY THE YEAR 2025, POSTMENOPAUSAL aged women will make up 20% of the U.S. population. In addition the incidence of obesity is also increasing. Obesity particularly contributes to the metabolic syndrome, which is an increasingly prevalent disorder that afflicts ϳ47 million people in the United States (2) and involves a clustering of risk factors for cardiovascular disease and type 2 diabetes. The incidence of diabetes seems to be slightly lower in women than men throughout most of life (37); however, as estrogen levels drop, the estrogen/androgen ratio changes in postmenopausal women, and a change in this ratio may affect cardiovascular disease and the metabolic syndrome (12,14,15). Indeed, postmenopausal women display an increased insulin resistance compared with premenopausal women, predisposing them to the development of diabetes.In animals, ovariec...

Aging of the world population and a concomitant increase in age-related diseases and disabilities mandates the search for strategies to increase healthspan, the length of time an individual lives healthy and productively. Due to the age-related decline of the immune system, infectious diseases remain among the top 5–10 causes of mortality and morbidity in the elderly, and improving immune function during aging remains an important aspect of healthspan extension. Calorie restriction (CR) and more recently rapamycin (rapa) feeding have both been used to extend lifespan in mice. Preciously few studies have actually investigated the impact of each of these interventions upon in vivo immune defense against relevant microbial challenge in old organisms. We tested how rapa and CR each impacted the immune system in adult and old mice. We report that each intervention differentially altered T-cell development in the thymus, peripheral T-cell maintenance, T-cell function and host survival after West Nile virus infection, inducing distinct but deleterious consequences to the aging immune system. We conclude that neither rapa feeding nor CR, in the current form/administration regimen, may be optimal strategies for extending healthy immune function and, with it, lifespan.

Changes in the estrogen/testosterone balance at menopause may negatively influence the development of diabetic kidney disease. Furthermore, recent studies suggest that changes in hormone levels during perimenopause may influence disease development. Injection of 4-vinylcyclohexene diepoxide (VCD) in B 6C3F1 mice induces gradual ovarian failure, preserving both the perimenopausal (peri-ovarian failure) and menopausal (post-ovarian failure) periods. To address the impact of the transition into menopause on the development of diabetes and diabetic kidney damage, we used streptozotocin (STZ)-induced diabetes in the VCD model of menopause. After 6 wk of STZ-induced diabetes, blood glucose was significantly increased in post-ovarian failure (post-OF) diabetic mice compared with cycling diabetic mice. In peri-ovarian failure (peri-OF) diabetic mice, blood glucose levels trended higher but were not significantly different from cycling diabetic mice, suggesting a continuum of worsening blood glucose across the menopausal transition. Cell proliferation, an early marker of damage in the kidney, was increased in post-OF diabetic mice compared with cycling diabetic mice, as measured by PCNA immunohistochemistry. In post-OF diabetic mice, mRNA abundance of early growth response-1 (Egr-1), collagen-4␣1, and matrix metalloproteinase-9 were increased and 3␤-hydroxysteroid dehydrogenase 4 (3␤-HSD4) and transforming growth factor-␤2 (TGF-␤2) were decreased compared with cycling diabetic mice. In peri-OF diabetic mice, mRNA abundance of Egr-1 and 3␤-HSD4 were increased, and TGF-␤2 was decreased compared with cycling diabetic mice. This study highlights the importance and utility of the VCD model of menopause, as it provides a physiologically relevant system for determining the impact of the menopausal transition on diabetes and diabetic kidney damage. diabetes; 3␤-HSD4; perimenopause; real-time PCR; estrogen DIABETES IS ONE OF THE MOST prevalent and costly diseases afflicting developed countries, with estimates placing the current global cost of diabetes at $150 billion a year (1). Approximately one-third of all diabetics die of end-stage renal disease (33) due to progressive renal damage and hypertension.17␤-Estradiol is considered protective against the development and progression of many diseases, including cardiovascular (9) and renal disease (34). Premenopausal women have slower rates of progression of nondiabetic renal disease than age-matched men (23), a difference that seems to disappear after menopause (3). The impact of estrogen on diabetic renal disease is less clear, however. Several studies demonstrate a decreased incidence of diabetic renal disease in women, but others have found no difference between men and women (34).The 5-10 years preceding menopause is termed perimenopause, and during this time estrogen levels fluctuate, with periods of low estrogen interspersed with periods of very high estrogen (31). The periods of low estrogen become more frequent as a woman approaches menopause until circulating levels of 17␤...

PurposeRecent studies suggest that the neural retinal response to light is compromised in diabetes. Electroretinogram studies suggest that the dim light retinal rod pathway is especially susceptible to diabetic damage. The purpose of this study was to determine whether diabetes alters rod pathway signaling.MethodsDiabetes was induced in C57BL/6J mice by three intraperitoneal injections of streptozotocin (STZ; 75 mg/kg), and confirmed by blood glucose levels > 200 mg/dL. Six weeks after the first injection, whole-cell voltage clamp recordings of spontaneous and light-evoked inhibitory postsynaptic currents from rod bipolar cells were made in dark-adapted retinal slices. Light-evoked excitatory currents from rod bipolar and AII amacrine cells, and spontaneous excitatory currents from AII amacrine cells were also measured. Receptor inputs were pharmacologically isolated. Immunohistochemistry was performed on whole mounted retinas.ResultsRod bipolar cells had reduced light-evoked inhibitory input from amacrine cells but no change in excitatory input from rod photoreceptors. Reduced light-evoked inhibition, mediated by both GABAA and GABAC receptors, increased rod bipolar cell output onto AII amacrine cells. Spontaneous release of GABA onto rod bipolar cells was increased, which may limit GABA availability for light-evoked release. These physiological changes occurred in the absence of retinal cell loss or changes in GABAA receptor expression levels.ConclusionsOur results indicate that early diabetes causes deficits in the rod pathway leading to decreased light-evoked rod bipolar cell inhibition and increased rod pathway output that provide a basis for the development of early diabetic visual deficits.