Aliskiren Attenuates the Inflammatory Response and Wound Healing Process in Diabetic Mice With Periodontal Disease

Author(s)

Penha Oliveira, Sandra Helena ^{[1, 2]} ; Balera Brito, Victor Gustavo ^{[1, 2]} ; Tfaile Frasnelli, Sabrina Cruz ^[1] ; Ribeiro, Bianca da Silva ^[1] ; Ferreira, Milena Nunes ^[1] ; Queiroz, Dayane Priscilla ^{[1, 2]} ; Beltan, Carluci Tais ^[1] ; Lara, Vanessa Soares ^[3] ; Santos, Carlos Ferreira ^[4]

Affiliation

^[1] Sao Paulo State Univ UNESP, Sch Dent Aracatuba, Dept Basic Sci, Sao Paulo - Brazil

^[2] Sao Paulo State Univ UNESP, Sch Dent Aracatuba, Programa Multictr Posgrad Ciencias Fisiol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Bauru Sch Dent, Dept Stomatol, Bauru - Brazil

^[4] Univ Sao Paulo, Bauru Sch Dent, Dept Biol Sci, Bauru - Brazil

• Document type: Journal article
• Source: FRONTIERS IN PHARMACOLOGY; v. 10, JUL 4 2019.
• Web of Science Citations: 1

Abstract

The aim of this study was to characterize the role of local RAS (renin-angiotensin system) in the inflammatory response of normal (N) and diabetic (D) mice with periodontal disease (PD). Diabetes Mellitus (DM) was induced by peritoneal injection of streptozotocin in Balb/c mice. PD was induced by ligature around the first molar in both N and D, irrespective of whether they were treated with aliskiren (50 mg/kg, Alisk). Mandibles were harvested for histomorphometric analyses, and gingival tissue (GT) was collected to evaluate gene expression and extracellular matrix components (ECM). Immunohistochemical (IHC) analyses were used to localize RAS in GT. The production of C-reactive protein (CRP), IL-1 beta, CXCL2, and CCL8 was evaluated by enzyme-linked immunosorbent assay (ELISA). Renin was found to exacerbate the inflammation and periodontal bone loss at 14 days after PD, and Alisk inhibited this process in GT of N and D. PD increased CRP, CXCL2, CCL8, and IL-1 beta production in both animals. Alisk could inhibit CRP, CXCL2, and CCL8 primarily in D animals. However, only CCL8 was decreased in N animals after Alisk pretreatment. PD enhanced expression and production of AGT, ACE, AT1R, and AT2R in both N and D. AT1R expression was higher in D with PD, and AT2R expression was higher in N with PD. ACE2 and receptor Mas (MasR) expression and production was elevated in the control group of both animals. PD inhibited ACE2 in N but not in D. MasR expression was unaffected in both N and D with PD. Alisk reduced expression and production of all RAS components in GT of both animals, except for ACE2 in N. RAS staining was observed in all layers of epithelium, basal cell layer, and lamina propria and was higher in N with PD. Col1a1, Col1a2, Col3a1, and fibronectin (Fn1) were increased in both animals with PD. Alisk inhibited Col1a1 and Fn in both animals, Col1a2 was decreased only in D, while levels of Col3a1 remained unchanged in all animal groups. In conclusion, these data demonstrated the presence and functional role of local RAS in GT, exacerbating the inflammatory response, periodontal bone loss, and wound healing processes in both N and D animal groups. In addition, Alisk was able to significantly reduce gingival inflammation, excessive wound healing processes, and periodontal bone loss. (AU)

• FAPESP's process: 18/04989-0 - The role of mast cells and their microRNAs on the inflammatory response and bone metabolism in diabetic mice with periodontitis
• Grantee: Milena Nunes Ferreira
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 17/05873-3 - In vitro analysis of mast cells and renin-angiotensin system role of spontaneously hypertensive animals osteoblasts and osteoclasts
• Grantee: Sabrina Cruz Tfaile Frasnelli
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/04476-3 - The role of renin on the production of Th17 cytokines, oxidative stress and antioxidants by gingival tissue from diabetic mice with periodontite
• Grantee: Bianca da Silva Ribeiro
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 15/03965-2 - Role of the renin-angiotensin system in different oral inflammatory models: an experimental interdisciplinary and clinical approach
• Grantee: Carlos Ferreira dos Santos
• Support Opportunities: Research Projects - Thematic Grants