Effect of mineralocorticoid receptor blockade on the renal renin-angiotensin system in Dahl salt-sensitive hypertensive rats.
BACKGROUND
The (pro)renin receptor exists in the kidney, blood vessels and the heart. (Pro)renin binds to the receptor and induces tissue injuries directly, completely independent of angiotensin II (Ang II). The renal renin-angiotensin-aldosterone system is activated in salt-sensitive hypertensive rats with in-vitro studies showing aldosterone increases angiotensin-converting enzyme (ACE) activity, renin production and angiotensin II type 1 receptor (AT1R) activity. However, the effect of blockade of mineralocorticoid receptor on the renal (pro)renin receptor, angiotensinogen, ACE and AT1R in Dahl salt-sensitive rats is unknown.


METHODS
The following parameters were measured in Dahl salt-sensitive rats and in Dahl salt-resistant rats fed high-salt or low-salt diets and treated for 8 weeks with or without eplerenone (100 mg/kg per day, orally): blood pressure, plasma renin activity, plasma aldosterone concentration, kidney weight and Ang II contents, urinary protein excretion, glomerular injury (assessed by semiquantitative morphometric analysis) and levels of expression in the kidney of (pro)renin receptor protein and messenger RNA (mRNA) for angiotensinogen, ACE and AT1R.


RESULTS
Dahl salt-sensitive rats fed a high-salt diet had increased kidney/body weight (175%) and urinary protein excretion (886%) and decreased plasma renin activity and plasma aldosterone concentration. The rats developed progressive sclerotic and proliferative glomerular changes, concomitant with increased expression of renal (pro)renin receptor protein and mRNA levels of angiotensinogen, ACE and AT1R and kidney Ang II content. Treatment with eplerenone in Dahl salt-sensitive rats was associated with significant improvements in kidney to body weight ratio, urinary protein excretion and renal injury scores and decreased renal (pro)renin receptor protein expression and angiotensinogen and AT1R mRNA levels and kidney Ang II content.


CONCLUSIONS
A high salt diet increased the renal renin-angiotensin system, whereas blockade of mineralocorticoid receptors attenuated renal injuries by decreasing the activity of tissue renin-angiotensin system in Dahl salt-sensitive rats.
Zhu
Aoshuang
A
Department of Internal Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Yoneda
Takashi
T
Demura
Masashi
M
Karashima
Shigehiro
S
Usukura
Mikiya
M
Yamagishi
Masakazu
M
Takeda
Yoshiyu
Y
D000818:Animals; D000077545:Eplerenone; D006973:Hypertension / Q000209:etiology*; D007668:Kidney / Q000187:drug effects*; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D012598:Sclerosis; D012982:Sodium, Dietary / Q000008:administration & dosage; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000093342:Prorenin Receptor
D000451:Mineralocorticoid Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D011956:Receptors, Cell Surface; D012982:Sodium, Dietary; D013148:Spironolactone; D000077545:Eplerenone; D000093342:Prorenin Receptor