Mineralocorticoid receptor--Rac1 activation and oxidative stress play major roles in salt-induced hypertension and kidney injury in prepubertal rats.
OBJECTIVE
To elucidate the roles that renal mineralocorticoid receptor-Rac1 interactions and oxidative stress play in salt-induced hypertension and renal injury in prepubertal rats.


METHODS
Three-week-old male Sprague Dawley rats were uninephrectomized (UNx) and fed a high-salt (8% NaCl) diet for 4 weeks. Five were left untreated, whereas the remaining rats were administered an mineralocorticoid receptor blocker (n = 5), a Rac1 inhibitor (n = 5), a Rho-kinase inhibitor (n = 5), or the superoxide dismutase mimetic tempol (n = 5). A control group of young UNx rats (n = 5) was fed a normal-salt (0.5% NaCl) diet. The rats were sacrificed after a 4-week experimental period. Blood pressure, urinary protein, histological morphology, and renal serum-regulated and glucocorticoid-regulated kinase (Sgk) 1 and Rac1 expression were evaluated. The effect of adrenalectomy with dexamethasone supplementation in young salt-loaded UNx rats (n = 5) was also evaluated.


RESULTS
Excessive salt intake induced hypertension and proteinuria in the young UNx rats, whose kidneys showed marked histological injury, Sgk1 overexpression and Rac1 activation. Both mineralocorticoid receptor blockade and Rac1 inhibition markedly prevented these abnormalities associated with a reduction in renal Rac1 expression. Adrenalectomy, but not Rho-kinase inhibition, also prevented salt-induced renal injury. Interestingly, tempol inhibited renal Rac1 activation and renal injury.


CONCLUSIONS
These findings suggest that Rac1-related mineralocorticoid receptor activation contributed to salt-induced hypertension and kidney injury in young UNx rats. Furthermore, as adrenalectomy abrogated salt-induced proteinuria, Rac1 may be an enhancer of aldosterone-induced mineralocorticoid receptor activation. Oxidative stress may also modify the interaction between Rac1 and mineralocorticoid receptor.
Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Kanagawa, Japan. hirookawarazaki@yahoo.co.jp
Hiroo
H
Kawarazaki
Katsuyuki
K
Ando
Shigeru
S
Shibata
Kazuhiko
K
Muraoka
Megumi
M
Fujita
Chiaki
C
Kawarasaki
Toshiro
T
Fujita
D000818:Animals; D015153:Blotting, Western; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology*; D007674:Kidney Diseases / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D009392:Nephrectomy; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012741:Sexual Maturation; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein