Age-related renal disease in female Dahl salt-sensitive rats is attenuated with 17 beta-estradiol supplementation by modulating nitric oxide synthase expression.
BACKGROUND
The incidence of chronic renal disease in women increases with aging, especially after menopause, suggesting that loss of sex hormones may contribute to the development and progression of renal disease. However, the mechanisms by which sex hormones, particularly estrogens, contribute to the disease process are unclear.


OBJECTIVE
The present study examined the effects of ovariectomy (OVX) with or without 17 beta-estradiol (E2) supplementation (OVX+E2) on the expression of inducible (iNOS) and endothelial (eNOS) nitric oxide synthase in the kidney.


METHODS
The study was performed in young (4 months [4M]) and aged (12 months [12M]) female Dahl salt-sensitive rats fed a low-sodium (0.1% NaCl) diet. At 3 months of age, the animals were either subjected to sham surgery, OVX, or OVX with implantation of an E2 silastic pellet. The treatments were administered for either 1 or 9 months, rendering the animals 4 months of age or 12 months of age at the time of sacrifice, respectively. Renal expression of NOS isoforms was measured by Western blotting and immunohistochemistry.


RESULTS
OVX in the aged rats was associated with 35% and 25% decreases in medullary iNOS (mean [SEM] relative optical density [ROD]: 4M OVX, 1.81 [0.14] vs 12M OVX, 1.17 [0.16]; P < 0.05) and eNOS (mean ROD: 4M OVX, 1.91 [0.09] vs 12M OVX, 1.43 [0.15]; P < 0.05) protein expression, respectively, and a 25-fold increase in the abundance of CD68-positive cells, indicating macrophage infiltration (mean cells/mm2: 4M OVX, 1.18 [0.09] vs 12M OVX, 30.0 [0.74]; P < 0.001). E2 supplementation either partially or completely attenuated these changes in iNOS (mean ROD: 4M OVX+E2, 2.26 [0.08] vs 12M OVX+E2, 1.70 [0.09]; P < 0.05), eNOS (mean ROD: 4M OVX+E2, 2.03 [0.07] vs 12M OVX+E2, 1.77 [0.11]; P = NS) and CD68 (mean cells/mm2: 4M OVX+E2, 1.46 [0.07] vs 12M OVX+E2, 6.87 [1.6]; P < 0.01) associated with OVX in the aging kidney.


CONCLUSIONS
These data suggest that ovarian E2 loss with aging may contribute to the development of age-related renal disease through downregulation of iNOS and eNOS protein abundance and increased renal inflammation in this animal model. Furthermore, E2 supplementation may be protective in the aging kidney by attenuating these changes.
Department of Medicine, Georgetown University Medical Center, Washington, DC, USA. cmaric@physiology.umsmed.edu <cmaric@physiology.umsmed.edu>
Christine
C
Maric
Qin
Q
Xu
Kathryn
K
Sandberg
Carmen
C
Hinojosa-Laborde
D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D004039:Diet, Sodium-Restricted; D004195:Disease Models, Animal; D015536:Down-Regulation; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects* / Q000378:metabolism; D017698:Postmenopause / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl
D004958:Estradiol; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III