OBJECTIVES: 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.
OBJECTIVES: 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.
Authors: Ana P Davel; Qing Lu; M Elizabeth Moss; Sitara Rao; Imran J Anwar; Jennifer J DuPont; Iris Z Jaffe Journal: J Am Heart Assoc Date: 2018-02-16 Impact factor: 5.501