Dual blockade of aldosterone and angiotensin II additively suppresses TGF-beta and NADPH oxidase in the hypertensive kidney.
BACKGROUND
Angiotensin II blockade and spironolactone effectively reduces proteinuria in humans. To clarify the mechanisms of the beneficial effect of blockade of both aldosterone and angiotensin II, we associated the aldosterone antagonist eplerenone to an angiotensin-converting enzyme inhibitor (ACEI) and examined the effect on renal transforming growth factor (TGF)-beta expression and oxidative stress by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the Dahl salt-sensitive rat with heart failure (DSHF).


METHODS
Dahl salt-resistant control rats and DSHF rats were fed with 8% NaCl diet and at 11 weeks the DSHF rats were treated with vehicle, eplerenone (Epl), trandolapril or a combination of both drugs for 7 weeks.


RESULTS
DSHF rats showed increased NADPH oxidase and decreased superoxide dismutase (SOD) resulting in increased oxidative stress. ACEI and Epl reduced NADPH oxidase showing an additive effect in their combination; ACEI increased manganese SOD (MnSOD) and Epl increased MnSOD, copper-zinc SOD and catalase, resulting in the lowest levels of oxidative stress with the combination therapy. Glomerulosclerosis and proteinuria were increased in the DSHF rats, and Epl suppressed them more effectively than ACEI to levels not different from the combination of both, showing a positive correlation with NADPH oxidase expression and TGF-beta. Renal TGF-beta was specifically suppressed with Epl


CONCLUSIONS
The association of Epl to ACEI is beneficial due to further reduction of NADPH oxidase and specific inhibition of TGF-beta resulting in improvement of renal damage.
Onozato
Maristela Lika
ML
Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Tojo
Akihiro
A
Kobayashi
Naohiko
N
Goto
Atsuo
A
Matsuoka
Hiroaki
H
Fujita
Toshiro
T
D000450:Aldosterone / Q000502:physiology; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002303:Cardiac Output, Low / Q000378:metabolism / Q000503:physiopathology; D004357:Drug Synergism; D000077545:Eplerenone; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D000451:Mineralocorticoid Receptor Antagonists; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C052035:trandolapril; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D000254:Sodium-Potassium-Exchanging ATPase