Background: Augmented sympathetic nerve activity (SNA) and renin-angiotensin-aldosterone system (RAAS) are involved in the pathogenesis of hypertension (HT) accompanied with chronic kidney disease (CKD). The oxidative stress in the hypothalamus in the brain increases SNA in HT. The renal denervation (RDN) or angiotensin receptor blocker (olmesartan; OLM) exerts an antihypertensive effect in HT with CKD; however, the precise mechanisms of the combination therapy are not fully elucidated. In the present study, we examined whether combining RDN and OLM reduces SNA through oxidative stress in the hypothalamus and RAAS in hypertensive mice with CKD. Methods and Results: In 5/6-nephrectomized ICR-mice (Nx, n=19) at 4-weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased (147±3 vs. 107±3mmHg, p<0.001), accompanied by increased SNA (urinary norepinephrine (uNE): 504±21 vs. 243±25μg/24hrs, p<0.001) and albuminuria (547±80 vs. 108±15mg/g creatinine, p<0.01) compared with those in control-mice (n=9). Nx-mice were orally-administered OLM (10mg/kg/day), vehicle, or performed RDN under OLM-administration, and divided into Nx-OLM (n=5), Nx-VEH (n=9), and Nx-OLM/RDN (n=5), respectively. In Nx-OLM and -OLM/RDN at 8-weeks after therapy, SBP were significantly decreased (124±3 and 116±3 vs. 144±2mmHg, n=5-9, p<0.05) accompanied with inhibition of both uNE (379±69 and 347±61 vs. 568±24μg/day, n=5-9, p<0.05) and oxidative stress in the hypothalamus (thiobarbituric acid-reactive substances: 0.952±0.06 and 1.012±0.041 vs. 1.222±0.047nmol/mg protein, n=5-9, p<0.05) compared with those in Nx-VEH, without worsening creatinine clearance. In Nx-OLM and -OLM/RDN, the albuminuria was also suppressed compared with that in Nx-VEH (476±56 and 499±82 vs. 1059±165mg/g creatinine, n=5-9, p<0.05). In Nx-OLM/RDN, but not in Nx-OLM, the plasma aldosterone concentration level was significantly decreased compared with that in Nx-VEH (441±35 vs. 675±33pg/ml, n=5-9, p<0.05). Conclusion: These findings suggest that the OLM/RDN combination therapy have a strong antihypertensive effect associated with inhibiting SNA through reducing oxidative stress in the brain and the plasma aldosterone in hypertensive mice with CKD.