The current study was designed to examine the protection of RAGE-specific inhibitor FPS-ZM1 against renal injury in spontaneously hypertensive rats (SHR) and investigate the underlying mechanism. The adult male SHR were treated with FPS-ZM1 via oral gavages for 12 weeks, and age-matched male Wistar-Kyoto rats (WKY) were used as control. Treatment of SHR with FPS-ZM1 slightly reduced blood pressure, and significantly improved baroreflex sensitivity in SHR. Treatment of SHR with FPS-ZM1 improved renal function, evidenced by increased glomerular filtration rate and renal blood flow, and reduced plasma creatinine, blood urea nitrogen and urine albumin excretion rate. Histology results revealed that treatment of SHR with FPS-ZM1 alleviated renal injury and reduced tubulointerstitial fibrosis. Treatment of SHR with FPS-ZM1 suppressed activation of NF-κB and reduced expression of pro-inflammatory cytokines including Tnf, Il6, and Il1b. Treatment of SHR with FPS-ZM1 abated oxidative stress and downregulated mRNA levels of components of NADPH oxidase (Nox) including Cyba, Nox1, Nox2, Nox4 and Ncf1 in kidneys. In addition, treatment of SHR with FPS-ZM1 reduced renal AngII levels, downregulated mRNA expression of Ace and upregulated expression of Agtr2. In conclusion, treatment with FPS-ZM1 alleviated hypertension-related renal dysfunction, possibly by suppressing NF-κB-mediated inflammation, abating Nox-mediated oxidative stress, and improving local renal renin-angiotensin system (RAS).