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

Abstract

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 β-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.

The Role of Age and Sex in Non-linear Dilution Adjustment of Spot Urine Arsenic

“…141–144 Any relative restriction of tubular function about glomerular filtration rate might thus align the excretion behaviors of CRN and TWuAs, translating into an approximation of b to 1. Age-related tubular renal damage progresses faster in males than in females, 136–139 which could conclusively explain the reemerging male-dominant age gap in exponents b at higher ages, as illustrated in Figure 6.…”

“…This inconsistency in men could be due to different age group distributions in the studies or intrinsic renal aging mechanisms, which are more pronounced in men and cause fluid homeostasis inelasticity, such as declining renal prostaglandin levels and tubular dysfunction. [134][135][136][137][138][139] While ATII/AVP activities increase with age, the paradoxical urinary concentrating ability deficit in seniors is likely due to these intrinsic renal causes. 135,140 In conclusion, the age-and sex-specific variations of exponent b consistently reflect the renal baseline actions of ATII/AVP, influenced by sex hormones in the young and renodegenerative changes in the elderly, irrespective of the age-related decline in renal concentrating capacity.…”

Impact of exercise training associated with enalapril treatment on blood pressure variability and renal dysfunctions in an experimental model of arterial hypertension and postmenopause

“…Finally, the female sex could be a protective factor to delayed the progression of the renal damage. Recently, Ansari et al [ 51 ] showed a sex and age-related progression of renal fibrosis. Specifically, no differences in renal fibrosis indices were observed between female rats at 6.5 and 8 months of age.…”

“…Specifically, no differences in renal fibrosis indices were observed between female rats at 6.5 and 8 months of age. In contrast, female showed a protective effect from renal damage in relation to age-matched males [ 51 ].…”

Tissue-specific expression of senescence biomarkers in spontaneously hypertensive rats: evidence of premature aging in hypertension

“…Specifically, males are at a higher risk of developing cardiovascular disease compared to age-matched premenopausal women. Moreover, male hypertensive rats displayed greater levels of fibrosis in the heart and kidney compared to female rats ( Ansari, Walton & Denton, 2023 ). However, the understanding mechanisms by which hypertension induces end-organ damages are not completely understood.…”