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  • Review Article
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Sexual dimorphism in the aging kidney: differences in the nitric oxide system

Nature Reviews Nephrology volume 5, pages 384–396 (2009)Cite this article

Abstract

Females—both rats and women—are substantially protected against the age-dependent decrease in renal function that occurs in males of the species. In part, this finding reflects the cardioprotective and renoprotective effects of estrogens, but estrogen has multiple actions, not all of which are beneficial. In addition, the low androgen level in women might be protective against a decline in renal function, but animal and clinical data on possible adverse effects of androgens are controversial. Androgens also have multiple actions, one of which—aromatization to estrogen—is likely to be protective. Sex steroids clearly have many complex actions, which explains the conflicting information on their relative benefits and dangers. Endothelial nitric oxide (NO) deficiency contributes importantly to cardiovascular risk and intrarenal NO deficiency is clearly linked to chronic kidney disease progression in animal models. Endothelial dysfunction develops with increasing age but is delayed in females, correlating with a delayed rise in asymmetric dimethylarginine level. There is no clear link between aging and arginine (the NO synthase substrate) deficiency. Animal data suggest that the aging kidney develops NO deficiency as a result of changes in neuronal NO synthase. The increased oxidative stress that occurs with aging affects multiple stages of the NO biosynthetic pathway and results in decreased production and/or action of NO. NO production is better preserved in females than in males, partly as a result of the actions of estrogens.

Key Points

  • The rate of loss of kidney function with aging should be slow—about 1% per year after age 40 in men; a more-rapid rate of loss probably reflects undiagnosed comorbidities

  • Women with a history of pre-eclampsia should be monitored as they age as they have a small but increased risk of developing kidney disease and end-stage renal disease

  • The sex hormones have complex and sometimes competing actions on cardiovascular and renal function and extrapolating from animal to clinical data is dangerous

  • Native estrogen is preferred to conjugated equine estrogens and transdermal or transvaginal administration is preferable to oral administration; de novo hormone replacement therapy should be administered cautiously after the onset of menopause

  • Prospective clinical studies are needed to specifically investigate the influence of androgen supplementation on cardiovascular and renal function in both aging men and women

  • Nitric oxide deficiency develops during aging, probably for multiple reasons, and contributes to both cardiovascular and renal dysfunction

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Figure 1: The association between age and relative GFR (measured by inulin clearance) in a | healthy men and b | healthy women (aged 21–67 years) who were evaluated as potential kidney transplant donors.
Figure 2: The association between age and relative ERPF (measured by para-aminohippurate clearance) in a | healthy men and b | healthy women (aged 21–67 years) who were evaluated as potential kidney transplant donors.
Figure 3: Graphs showing a | GFR (from inulin clearances), b | percentage glomerulosclerosis and c | glomerular BP in 18–20-month-old intact males, intact females, castrated males and ovariectomized females of the Munich–Wistar rat strain.
Figure 4: Graphs showing a | 24 h urinary nitric oxide excretion (UNOxV) and b | glomerular injury, in young (aged 3–5 months) and old (18–22 months) male and female Sprague–Dawley rats.
Figure 5: Simplified scheme showing the biosynthetic pathway for in vivo NO production and possible mechanisms of NO deficiency.
Figure 6: Regression analysis of ADMA levels and age in a | female and b | male healthy, non-smoking, non-obese individuals aged 19–75 years.
Figure 7: The relative abundance of nNOS α protein in homogenates of renal cortex from young, middle-aged and old male and female Sprague–Dawley rats.

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  1. C. Baylis, Department of Physiology and Functional Genomics, Department of Medicine, 1600 SW Archer Road, University of Florida, PO Box 100274, Gainesville, FL 32667, USA baylisc@ufl.edu

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    Chris Baylis

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Baylis, C. Sexual dimorphism in the aging kidney: differences in the nitric oxide system. Nat Rev Nephrol 5, 384–396 (2009). https://doi.org/10.1038/nrneph.2009.90

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