Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Kanagawa, Japan.
J Hypertens. 2012 Oct;30(10):1977-85. doi: 10.1097/HJH.0b013e3283576904.
To elucidate the roles that renal mineralocorticoid receptor-Rac1 interactions and oxidative stress play in salt-induced hypertension and renal injury in prepubertal rats.
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.
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.
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.
阐明肾矿物ocorticoid 受体-Rac1 相互作用和氧化应激在未成年大鼠盐诱导高血压和肾损伤中的作用。
3 周龄雄性 Sprague Dawley 大鼠行单侧肾切除术（UNx）并给予高盐（8%NaCl）饮食 4 周。其中 5 只未予治疗，其余大鼠分别给予矿物ocorticoid 受体阻滞剂（n=5）、Rac1 抑制剂（n=5）、Rho-激酶抑制剂（n=5）或超氧化物歧化酶模拟物 Tempo（n=5）。年轻 UNx 大鼠的对照组（n=5）给予正常盐（0.5%NaCl）饮食。实验 4 周后处死大鼠。评估血压、尿蛋白、组织形态学及肾血清调节和糖皮质激素调节激酶（Sgk）1 和 Rac1 表达。还评估了年轻盐负荷 UNx 大鼠肾上腺切除术加地塞米松补充（n=5）的效果。
高盐摄入诱导年轻 UNx 大鼠发生高血压和蛋白尿，其肾脏出现明显的组织学损伤、Sgk1 过表达和 Rac1 激活。矿物ocorticoid 受体阻断和 Rac1 抑制均可显著预防这些与肾 Rac1 表达减少相关的异常。肾上腺切除术而非 Rho-激酶抑制也可预防盐诱导的肾损伤。有趣的是，Tempo 抑制了肾 Rac1 激活和肾损伤。
这些发现表明 Rac1 相关的矿物ocorticoid 受体激活参与了年轻 UNx 大鼠盐诱导的高血压和肾脏损伤。此外，由于肾上腺切除术消除了盐诱导的蛋白尿，Rac1 可能是醛固酮诱导的矿物ocorticoid 受体激活的增强剂。氧化应激也可能改变 Rac1 与矿物ocorticoid 受体的相互作用。
