Sexual Dimorphism in Development of Kidney Damage in Aging Fischer-344 Rats

Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA.
Gender Medicine (Impact Factor: 2.26). 07/2012; 9(4):219-31. DOI: 10.1016/j.genm.2012.06.003
Source: PubMed


Aging kidneys exhibit slowly developing injury and women are usually protected compared with men, in association with maintained renal nitric oxide.
Our purpose was to test 2 hypotheses: (1) that aging intact Fischer-344 (F344) female rats exhibit less glomerular damage than similarly aged males, and (2) that loss of female ovarian hormones would lead to greater structural injury and dysregulation of the nitric oxide synthase (NOS) system in aging F344 rat kidneys.
We compared renal injury in F344 rats in intact, ovariectomized, and ovariectomized with estrogen replaced young (6 month) and old (24 month) female rats with young and old intact male rats and measured renal protein abundance of NOS isoforms and oxidative stress.
There was no difference in age-dependent glomerular damage between young or old intact male and female F344 rats, and neither ovariectomy nor estrogen replacement affected renal injury; however, tubulointerstitial injury was greater in old males than in old females. These data suggest that ovarian hormones do not influence these aspects of kidney aging in F344 rats and that the greater tubulointerstitial injury is caused by male sex. Old males had greater kidney cortex NOS3 abundance than females, and NOS1 abundance (alpha and beta isoforms) was increased in old males compared with both young males and old females. NOS abundance was preserved with age in intact females, ovariectomy did not reduce NOS1 or NOS3 protein abundance, and estrogen replacement did not uniformly elevate NOS proteins, suggesting that estrogens are not primary regulators of renal NOS abundance in this strain. Nicotinamide adenine dinucleotide phosphate oxidase-dependent superoxide production and nitrotyrosine immunoreactivity were increased in aging male rat kidneys compared with females, which could compromise renal nitric oxide production and/or bioavailability.
The kidney damage expressed in aging F344 rats is fairly mild and is not related to loss of renal cortex NOS3 or NOS1 alpha.

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    • "Other notable functional deficits in the rat include proteinuria and reduced urine concentration (Haley and Bulger 1983; Sands 2003). Of note, the development of renal disease is more severe in males as compared to females (Baylis 1994; Sasser et al. 2012), and that nutrition affects age-related renal dysfunction (Zawada et al. 1997). In male Fischer 344 rats, we observe a progression of kidney deterioration similar to end-stage renal disease including severe glomerulosclerosis and interstitial fibrosis (Corman and Owen 1992). "
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    Preview · Article · May 2014 · AJP Regulatory Integrative and Comparative Physiology
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    ABSTRACT: Background: We previously reported that sexually mature female spontaneously hypertensive rats (SHRs) have greater nitric oxide (NO) synthase (NOS) enzymatic activity in the renal inner medulla (IM), compared to age-matched males. However, the mechanisms responsible for this sexual dimorphism are unknown. The current study tested the hypothesis that sex differences in renal IM NOS activity and NOS1 expression in adult SHRs develop with sexual maturation and increases in blood pressure (BP) in a female sex hormone-dependent manner. Methods and results: Renal IM were isolated from sexually immature 5-week-old and sexually mature 13-week-old male and female SHRs. Whereas NOS activity and NOS1 expression were comparable in 5- and 13-week-old male SHRs and 5-week-old female SHRs, 13-week-old females had greater NOS activity and NOS1 expression, compared to 5-week-old female SHRs and age-matched males. NOS3 expression was greater in 5-week-old than 13-week-old SHRs regardless of sex. Treatment with antihypertensive therapy (hydrochlorothiazide and reserpine) from 6 to 12 weeks of age to attenuate age-related increases in BP abolished the sex difference in NOS activity and NOS1 expression between sexually mature SHR males and females. To assess the role of female sex hormones in age-related increases in NOS, additional females were ovariectomized (OVX), and NOS activity was studied 8 weeks post-OVX. OVX decreased NOS activity and NOS1 expression. Conclusions: The sex difference in renal IM NOS in SHR is mediated by a sex hormone- and BP-dependent increase in NOS1 expression and NOS activity exclusively in females.
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