Sex- and age-related differences in renal and cardiac injury and senescence in stroke-prone spontaneously hypertensive rats.

BACKGROUND: Sex differences play a critical role in the incidence and severity of cardiovascular diseases, whereby men are at a higher risk of developing cardiovascular disease compared to age-matched premenopausal women. Marked sex differences at the cellular and tissue level may contribute to susceptibility to cardiovascular disease and end-organ damage. In this study, we have performed an in-depth histological analysis of sex differences in hypertensive cardiac and renal injury in middle-aged stroke-prone spontaneously hypertensive rats (SHRSPs) to determine the interaction between age, sex and cell senescence. METHODS: Kidneys, hearts and urine samples were collected from 6.5- and 8-month-old (Mo) male and female SHRSPs. Urine samples were assayed for albumin and creatinine content. Kidneys and hearts were screened for a suite of cellular senescence markers (senescence-associated ß-galactosidase, p16INK4a, p21, γH2AX). Renal and cardiac fibrosis was quantified using Masson's trichrome staining, and glomerular hypertrophy and sclerosis were quantified using Periodic acid-Schiff staining. RESULTS: Marked renal and cardiac fibrosis, concomitant with albuminuria, were evident in all SHRSPs. These sequelae were differentially affected by age, sex and organ. That is, the level of fibrosis was greater in the kidney than the heart, males had greater levels of fibrosis than females in both the heart and kidney, and even a 6-week increase in age resulted in greater levels of kidney fibrosis in males. The differences in kidney fibrosis were reflected by elevated levels of cellular senescence in the kidney in males but not females. Senescent cell burden was significantly less in cardiac tissue compared to renal tissue and was not affected by age or sex. CONCLUSIONS: Our study demonstrates a clear sex pattern in age-related progression of renal and cardiac fibrosis and cellular senescence in SHRSP rats. A 6-week time frame was associated with increased indices of cardiac and renal fibrosis and cellular senescence in male SHRSPs. Female SHRSP rats were protected from renal and cardiac damage compared to age-matched males. Thus, the SHRSP is an ideal model to investigate the effects of sex and aging on organ injury over a short timeframe.

Kidney and cardiovascular diseases are some of the leading causes of death worldwide, and they affect men and women differently. Young men are generally at higher risk of developing these diseases than young women. Women also have unique risk factors for kidney and cardiovascular disease. These may include complications associated with pregnancy, such as preeclampsia, and menopause. For example, the risk of disease for women increases significantly after menopause. In addition, treatment strategies for kidney and cardiovascular diseases are often less effective in women compared to men, but the causes for this are unknown. More research is needed to understand sex differences in kidney and cardiovascular diseases, so that we can develop new drugs that are effective in women as well as men. In this study, we have examined kidney and heart damage associated with elevated blood pressure in adult male rats and adult female rats (long before the onset of menopause). We have shown that males develop significantly more scarring of their hearts and kidneys compared to females. We also identified the cells in the kidneys of male rats, but not female rats, showed signs of DNA damage and early ageing. This suggests cellular damage in young males may contribute to their more rapid progression of kidney disease compared to females. Future research examining females after menopause, when disease risk is greater, will enhance our understanding of cell damage in kidney and cardiovascular disease.

Strategies for immortalisation of amnion-derived mesenchymal and epithelial cells.

Mesenchymal (human amniotic mesenchymal stem cell [HAMSC]) and epithelial cells (human amnion epithelial cell [HAEC]) derived from human amniotic membranes possess characteristics of pluripotency. However, the pluripotency of HAMSC and HAEC are sustained only for a finite period. This in vitro cell growth can be extended by cell immortalisation. Many well-defined immortalisation systems have been used for artificially overexpressing genes such as human telomerase reverse transcriptase in HAMSC and HAEC leading to controlled and prolonged cell proliferation. In recent years, much progress has been made in our understanding of the cellular machinery that regulates the cell cycle when immortalised. This review summarises the current understanding of molecular mechanisms that contribute to cell immortalisation, the strategies that have been employed to immortalise amnion-derived cell types, and their likely applications in regenerative medicine.

Insulin-regulated aminopeptidase deficiency impairs cardiovascular adaptations and placental development during pregnancy.

Insulin-regulated aminopeptidase (IRAP), an enzyme that cleaves vasoactive peptides including oxytocin and vasopressin, is suggested to play a role in pregnancy and the onset of preeclampsia. Our aim was to examine the contribution of IRAP to arterial pressure regulation and placental development during pregnancy in mice. Mean arterial pressure and heart rate were measured via radiotelemetry in 12-week-old female wild-type and IRAP knockout mice. Females were time-mated with males of the same genotype. Placentae were collected at embryonic day 18.5 for histological analysis. Basal heart rate was ∼40 bpm lower in IRAP knockout females compared with wild-type females. The increase in heart rate across gestation was greater in IRAP knockout females than wild-type females. Neither basal nor gestational mean arterial pressure was different between wildtype and IRAP knockout females. Urine output and water intake of IRAP knockout mice were ∼45% less than wild-type mice at late gestation. IRAP deficiency had no effect on fetal weight. Morphological assessment of placentae revealed that IRAP deficiency was associated with reduced labyrinth surface area and accumulation of glycogen in the junctional zone. Our data demonstrate that IRAP deficiency alters maternal fluid handling and impairs placental labyrinth expansion at late gestation, indicating that IRAP contributes to the normal adaptions to pregnancy.

Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease.

In mammals, seven members of the sirtuin protein family known as class III histone deacetylase have been identified for their characteristic features. These distinguished characteristics include the tissues where they are distributed or located, enzymatic activities, molecular functions, and involvement in diseases. Among the sirtuin members, SIRT3 has received much attention for its role in cancer genetics, aging, neurodegenerative disease, and stress resistance. SIRT3 controls energy demand during stress conditions such as fasting and exercise as well as metabolism through the deacetylation and acetylation of mitochondrial enzymes. SIRT3 is well known for its ability to eliminate reactive oxygen species and to prevent the development of cancerous cells or apoptosis. This review article provides a comprehensive review on numerous (noteworthy) molecular functions of SIRT3 and its effect on cancer cells and various diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease.

Emblica officinalis improves glycemic status and oxidative stress in STZ induced type 2 diabetic model rats.

OBJECTIVE: To evaluate the antidiabetic and antioxidant potential of Emblica officinalis (E. officinalis) fruit on normal and type 2 diabetic rats. METHODS: Type 2 diabetes was induced into the male Long-Evans rats. The rats were divided into nine groups including control groups receiving water, type 2 diabetic controls, type 2 diabetic rats treated with glibenclamide (T2GT) and type 2 diabetic rats treated with aqueous extract of fruit pulp of E. officinalis. They were fed orally for 8 weeks with a single feeding. Blood was collected by cutting the tail tip on 0 and 28 days and by decapitation on 56 day. Packed red blood cells and serum were used for evaluating different biochemical parameters. RESULTS: Four weeks administration of aqueous extract of E. officinalis improved oral glucose tolerance in type 2 rats and after 8 weeks it caused significant (P<0.007) reduction in fasting serum glucose level compared to 0 day. Triglycerides decreased by 14% but there was no significant change in serum ALT, creatinine, cholesterol and insulin level in any group. Furthermore, reduced erythrocyte malondialdehyde level showed no significant change (P<0.07) but reduced glutathione content was found to be increased significantly (P<0.05). CONCLUSIONS: The aqueous extract of E. officinalis has a promising antidiabetic and antioxidant properties and may be considered for further clinical studies in drug development.