Female protection in progressive renal disease is associated with estradiol attenuation of superoxide production.
BACKGROUND
Several types of renal disease progress at a faster rate in men compared with women, but the reasons for this sex difference are not well understood. Chronic renal disease is associated with elevated levels of toxic reactive oxygen species (ROS). Superoxide, the major ROS in the kidney, is generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.


OBJECTIVE
To determine if female protection from renal disease progression is consistent with 17beta-estradiol (E2) attenuation of superoxide production, this study was conducted to assess superoxide production in the renal cortex of male and female control and renal wrap (RW) rats, as well as in ovariectomized rats treated with vehicle or E2.


METHODS
Sprague-Dawley rats were divided into 2 sham operation male (Sham-M) and female (Sham-F) control groups, and 4 RW hypertensive groups: RW-M; RW-F; RW ovariectomized females treated with vehicle (RW-OVX); and RW ovariectomized females treated with E2, supplied as a 0.24 mg/60-day release pellet (RW-OVX+E2). All groups were maintained on a high-sodium (4% NaCl) diet for 6 weeks.


RESULTS
Mean (SEM) markers of renal injury and oxidative stress, including urinary protein (mg/24 h: RW-M, 298 [31] vs RW-F, 169 [22]; P < 0.001), microalbuminuria (RW/Sham arbitrary units [AU]/24 h: M, 8.78 [0.58] vs F, 4.31 [1.0]; P < 0.005), and malondialdehyde (nmol/24 h: RW-M, 167 [23] vs RW-F, 117 [8.5]; P < 0.05) levels, as well as mean glomerular volume (microm3 x 10(6): RW-M, 2.25 [0.16] vs RW-F, 1.25 [0.04]; P < 0.001) and the glomerulosclerotic index (AU: RW-M, 2.64 [0.19] vs RW-F, 1.10 [0.09]; P < 0.001) were greater in both control and RW males compared with females in the same treatment groups. Though RW surgery increased mean arterial pressure in both male and female rats, no sex difference was observed. Under these conditions, mean (SEM) renal cortical NADPH oxidase activity was 1.3-fold higher in RW males compared with RW females (relative light units [RLU]/180 sec: RW-M, 4080 [240] vs RW-F, 3200 [260]; P < 0.05). Ovariectomy increased NADPH oxidase activity by 1.4-fold (RLU/180 sec: RW-OVX, 4520 [184]; P < 0.01) under conditions in which the mean glomerular volume and glomerulosclerotic index were both increased by 1.5-fold, whereas E2 replacement (RLU/180 sec: RW-OVX+E2, 2745 [440]) prevented these effects. Furthermore, the effects on NADPH oxidase activity were mirrored by changes in the protein abundance of NADPH oxidase subunit p22P(phox).


CONCLUSIONS
These results suggest that E2 protects the female kidney in part by attenuating injury-induced increases in renal superoxide production.
Ji
Hong
H
Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University, Washington, DC 20057, USA. jih@georgetown.edu
Zheng
Wei
W
Menini
Stefano
S
Pesce
Carlo
C
Kim
James
J
Wu
Xie
X
Mulroney
Susan E
SE
Sandberg
Kathryn
K
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018450:Disease Progression; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D006977:Hypertension, Renal / Q000503:physiopathology*; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D010052:Ovariectomy; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*; D012737:Sex Factors; D013481:Superoxides / Q000378:metabolism*
D015415:Biomarkers; D013481:Superoxides; D004958:Estradiol; D019255:NADPH Oxidases