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

BackgroundSex 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.MethodsKidneys, 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 beta-galactosidase, p16(INK4a), p21, gamma H2AX). Renal and cardiac fibrosis was quantified using Masson's trichrome staining, and glomerular hypertrophy and sclerosis were quantified using Periodic acid-Schiff staining.ResultsMarked 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.ConclusionsOur 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. Plain Language SummaryKidney 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.

Automated summary

Sex differences play a critical role in cardiovascular diseases, with men at higher risk than premenopausal women. This study analyzed sex differences in hypertensive cardiac and renal injury in middle-aged SHRSP rats to determine the interaction between age, sex, and cell senescence. The results showed that male rats had greater levels of fibrosis and cellular senescence in the kidney compared to females, indicating a clear sex pattern in age-related progression of organ damage.