Sexual dimorphism in the aging kidney: differences in the nitric oxide system

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.