Periodontitis is an osteolytic disease characterized by destruction of the tooth-supporting tissues determined by cytokines induced by T-cells activation by oral bacteria products. Receptor activator of NF-kB Ligand (RANKL) stimulates bone resorption, while its soluble decoy receptor osteoprotegerin (OPG) blocks its action. RANKL activates its receptor (RANK) on monocytic precursors, triggering their differentiation into osteoclasts. Evidence indicates that Toll-like receptor (TLR) signaling regulates bone metabolism. TLRs are expressed in periodontal tissues and triggers a variety of downstream signal transduction pathways, including p-38 MAPK and NF-kB, which controls genes expression linked to inflammation and bone remodeling. Angiotensin II (ANG II) is now considered a pro-inflammatory cytokine since AT1 receptor (AT1R) blockade decreases the progression of inflammatory pathologies. The role of ANGII/AT1R in the periodontal disease is not known. We assessed the effect of valsartan (VAL), an AT1R blocker, on osteoclasts number, RANK/RANKL/OPG system expression, AT1 and TLR-4, and phosphorylation of p38-MAPK and NF-kB, in an experimental model of periodontitis induced by lipopolysaccharide (LPS) in rat. Experiments were conducted according to good practice for the management of laboratory animals of the Bolivarian Republic of Venezuela and the approval of Animal Ethical Committee of the School of Pharmacy. Male SD rats (280-300g) were divided into 4 groups: Control, LPS, VAL, LPS+VAL. LPS interdaily injections (10ul) and VAL (20 mg/kg, p.o.)/7 days were applied. Rats were anesthetized with 10% ketamine (60 mg/kg) and euthanized by decapitation, the maxilla dissected and the connective tissue collected. Immunofluorescent staining was used. Immunostaining was visualized with a confocal microscope. Intensity was quantified with NIH Image J software in 3 representative sections. Values are means ± SEM compared by ANOVA. LPS induced the formation of TRAP-positive multinucleated cells, increased tissue AT1R expression (C=3648±209; LPS=6081±150; L+V=4054±300) and TLR-4 (C=5487±66; LPS=7276±293; L+V=6097±62), RANK/RANKL system (C=5067±34; LPS=6161±48; L+V=5387±48/C=5570±130; LPA=7341±122; L+V=6177±189) and diminished OPG expression (C=5451±181; LPS=1007±42; L+V=5638±108). Also, LPS increased p-p38/p38 (C=1; LPS=1.52; L+V=1.19) and p-NF-kB/NF-kB (C=1; LPS=1.72; L+V=1.1). Conversely, VAL blunted all LPS-induce effects. Our results suggest that LPS, through TLR-4 stimulates MAPK and NF-kB-depentent pathways to induce bone resorption. Our data demonstrate a novel role for ANG II and AT1R in the pathogenesis of periodontal disease.