Estrogen and angiotensin II interactions determine cardio-renal damage in Dahl salt-sensitive rats with heart failure.
In women, the role of estrogen in the interrelationship between the progression of kidney and cardiac diseases is not fully understood. The present study attempted to elucidate the relationship between the process of cardiac remodeling and nephrosclerosis in ovariectomized Dahl salt-sensitive (DSS) rats with myocardial infarction (MI).


METHODS
60 DSS rats with MI produced by ligation of the left coronary artery were divided into 5 groups as follows: group 1: MI rats without ovariectomy (OVX); group 2: MI rats with OVX; group 3: MI and OVX rats with estradiol (E) (17beta-estradiol 15 mg/pellet/90 days subcutaneous pellet) supplementation; group 4: MI rats with OVX administered an angiotensin receptor antagonist (ARB), olmesartan, (2.5 mg/kg b.w. per day), and group 5: MI and OVX rats with E supplementation and administration of ARB in combination. Two weeks after ligation of the left coronary artery, OVX was carried out; this marked the start of the experiment. Body weight, systolic blood pressure (SBP), and urinary protein excretion were measured every 2 weeks for 12 weeks. Transthoracic echocardiogram was performed under anesthesia at 12 weeks. Blood samples for measurement of plasma renin activity, angiotensin (Ang) II, and aldosterone were obtained. At the end of the study, the heart and the kidney tissues were collected for light microscopic examination and evaluations of the expression of mRNA of angiotensin-converting enzyme and endothelial nitric oxide synthase (ecNOS).


RESULTS
SBP in female DSS rats with MI and with or without OVX transiently increased at week 4 and then gradually decreased toward the end of the study. Administration of ARB reduced SBP significantly (p < 0.05) in rats with OVX independently of E supplementation. OVX significantly (p < 0.05) increased and E supplementation further increased (p < 0.01) urinary protein excretion. E supplementation plus ARB administration significantly decreased urinary protein excretion. OVX increased activity in renin-angiotensin-aldosterone system (RAS) and both E and ARB supplementation suppressed RAS (p < 0.05). Expression of ecNOS was decreased in the rats with OVX and this was reversed by E supplementation in the heart but not in the kidneys, although combined administration with ARB reversed it in the kidney (p < 0.01). Transthoracic echocardiogram showed decreased ejection fraction by OVX and it was reversed by E supplementation and administration of ARB. Pathological changes of the kidney showed that E supplementation produced thrombotic microangiopathic lesions in the glomeruli. These changes were reversed by concomitant administration of ARB.


CONCLUSIONS
Although estrogen appears to protect the development of cardiac remodeling and heart failure, it promotes microangiopathy in the kidney due to thrombosis. Concomitant administration of estrogen and ARB might be effective for protection of the heart and the kidney in OVX DSS rats with CHF.
Hoshi-Fukushima
Rie
R
Department of Nephrology, Saitama Medical University, Saitama, Japan.
Nakamoto
Hidetomo
H
Imai
Hiroe
H
Kanno
Yoshihiko
Y
Ishida
Yuji
Y
Yamanouchi
Yasuhiro
Y
Suzuki
Hiromichi
H
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D003404:Creatinine / Q000097:blood / Q000652:urine; D004452:Echocardiography; D004958:Estradiol / Q000097:blood; D004967:Estrogens / Q000502:physiology*; D005260:Female; D007668:Kidney / Q000473:pathology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D009400:Nephrosclerosis / Q000473:pathology / Q000503:physiopathology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010052:Ovariectomy; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011507:Proteinuria / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D012084:Renin-Angiotensin System / Q000502:physiology*; D014599:Uterus / Q000473:pathology; D020257:Ventricular Remodeling / Q000502:physiology*
D004967:Estrogens; D012333:RNA, Messenger; D004958:Estradiol; D003404:Creatinine; D052250:Nitric Oxide Synthase Type III; D007703:Peptidyl-Dipeptidase A