Aberrant ENaC activation in Dahl salt-sensitive rats.
BACKGROUND
The epithelial sodium channel (ENaC) plays an important role in the regulation of blood pressure by modulating Na reabsorption in the kidney. Dahl salt-sensitive rats on high-salt diet develop severe hypertension, and high-salt diet has been reported to stimulate ENaC mRNA expression in the kidney abnormally in Dahl salt-sensitive rats despite a suppressed plasma aldosterone concentration (PAC).


METHODS
We investigated the effect of high-salt diet on ENaC protein expression in Dahl salt-resistant and Dahl salt-sensitive rats, and examined the effect of amiloride (5 mg/kg per day) and eplerenone (0.125% diet) on blood pressure and renal injury in Dahl salt-sensitive rats.


RESULTS
Dahl salt-sensitive rats developed hypertension and renal damage following 4 weeks of treatment with high-salt diet. Although PAC and kidney aldosterone content were all suppressed by the high-salt diet in Dahl salt-sensitive rats, both beta and gammaENaC mRNA expression and protein abundance were significantly increased. The molecular weight shift of gammaENaC from 85 to 70 kDa, an indication of ENaC activation, was clearly increased in Dahl salt-sensitive rats on high-salt diet compared with the low-salt group or Dahl salt-resistant rats on high-salt diet. Four weeks of treatment with amiloride, but not eplerenone, significantly ameliorated hypertension and kidney injury in Dahl salt-sensitive rats fed high-salt diet, suggesting aberrant aldosterone-independent activation of ENaC.


CONCLUSIONS
These results suggest that inappropriate expression and activation of ENaC could be one of the underlying mechanisms by which Dahl salt-sensitive rats develop salt-sensitive hypertension and organ damage, and indicate a therapeutic benefit of amiloride in salt-sensitive hypertension where ENaC is excessively activated.
Kakizoe
Yutaka
Y
Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
Kitamura
Kenichiro
K
Ko
Takehiro
T
Wakida
Naoki
N
Maekawa
Ai
A
Miyoshi
Taku
T
Shiraishi
Naoki
N
Adachi
Masataka
M
Zhang
Zheng
Z
Masilamani
Shyama
S
Tomita
Kimio
K
D000450:Aldosterone / Q000032:analysis; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D053503:Epithelial Sodium Channels / Q000032:analysis / Q000235:genetics*; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism; D007668:Kidney / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020303:Rats, Inbred Dahl; D012697:Serine Endopeptidases / Q000032:analysis / Q000652:urine; D000099271:Prostasin
D000450:Aldosterone; D053503:Epithelial Sodium Channels; D012333:RNA, Messenger; D012697:Serine Endopeptidases; D000099271:Prostasin