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

Jennifer M. Sasser PhD , Oladele Akinsiku , Natasha C. Moningka PhD , Katie Jerzewski , Chris Baylis PhD , Amanda J. LeBlanc PhD , Lori S. Kang PhD , Amy L. Sindler PhD , Judy M. Muller-Delp PhD
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引用次数: 10

Abstract

Background

Aging kidneys exhibit slowly developing injury and women are usually protected compared with men, in association with maintained renal nitric oxide.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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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衰老fisher -344大鼠肾损伤发育中的两性异形现象
衰老的肾脏表现出缓慢发展的损伤,与男性相比,女性通常受到保护,这与维持肾脏一氧化氮有关。我们的目的是验证两个假设:(1)衰老完整的fisher -344 (F344)雌性大鼠的肾小球损伤比同样年龄的雄性大鼠要小;(2)雌性卵巢激素的丧失会导致F344大鼠肾脏更大的结构损伤和一氧化氮合酶(NOS)系统的失调。方法将F344大鼠的肾损伤与未切除卵巢、未切除卵巢、未切除卵巢的雌性大鼠(6月龄)和雄性大鼠(24月龄)进行比较,测定NOS异型体的肾脏蛋白丰度和氧化应激水平。结果F344大鼠的年龄依赖性肾小球损伤在年轻和年老的完整雌雄大鼠之间无差异,卵巢切除和雌激素替代均不影响肾损伤;然而,老年男性的小管间质损伤大于老年女性。这些数据表明卵巢激素不影响F344大鼠肾老化的这些方面,更大的小管间质损伤是由雄性引起的。老年男性肾皮质NOS3丰度高于女性,NOS1丰度(α和β同型)在老年男性中均高于年轻男性和老年女性。在完整雌性中,NOS丰度随年龄保持不变,卵巢切除术不降低NOS1或NOS3蛋白丰度,雌激素替代不均匀升高NOS蛋白,提示雌激素不是该菌株肾脏NOS丰度的主要调节因子。与雌性相比,衰老的雄性大鼠肾脏中烟酰胺腺嘌呤二核苷酸磷酸氧化酶依赖的超氧化物产生和硝基酪氨酸免疫反应性增加,这可能会损害肾脏一氧化氮的产生和/或生物利用度。结论F344衰老大鼠肾损伤程度较轻,与肾皮质NOS3或NOS1 α的丧失无关。
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Gender Medicine
Gender Medicine 医学-医学:内科
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