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

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-1β, 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-1β 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.

Telmisartan Prevents Alveolar Bone Loss by Decreasing the Expression of Osteoclasts Markers in Hypertensive Rats With Periodontal Disease

“…The present study results demonstrated that the AT1R blocker, TELM, had a protective effect on PD-induced inflammation and alveolar bone loss in hypertensive animals by decreasing the production of cytokines and reducing the expression of osteoclast markers in hypertensive animals. The action of the local RAS in periodontal tissues has already been described and is associated with periodontal inflammatory damage (Santos et al, 2009;Santos et al, 2015;Dionisio et al, 2019;Oliveira et al, 2019). The SHR strain is known to present alterations in the systemic RAS (Schiffrin et al, 1984;Ohta et al, 1996;Gouldsborough et al, 2003) as well as intrinsic bone impairment associated with the hypertensive genotype and phenotype (Manrique et al, 2012;Landim de Barros et al, 2016;Tiyasatkulkovit et al, 2019).…”

“…For IHC analysis, slides were blindly analyzed (n 5/group) in 400× magnification bright-field microscopy (Olympus, BX53, Tokyo, Japan) in the region of interest (middle third of the first molar furcation region), and expression was based on the immunostaining pattern [negative (−); low staining (+); moderate staining (++); strong staining (+++)] (Oliveira et al, 2019). To compose the presented image boards, a representative section was photographed (Olympus, XC50, Tokyo, Japan), in the analyzed region of interest (400× magnification and detailed 1,000× magnification).…”

“…We have previously reported that SHRs suffer from more severe periodontal inflammation (Bonato et al, 2012), and the inhibition of the RAS can attenuate the resorption of alveolar bone (Dionisio et al, 2019;Oliveira et al, 2019). In this study, we aimed to evaluate the local bone metabolism of normotensive and hypertensive animals with PD following treatment with TELM, as the effects of TELM on bone metabolism are yet to be clearly understood.…”

<p>The Anti-Inflammatory Effect of Different Doses of Aliskiren in Rat Models of Inflammation</p>

“…7 Renin can exacerbate the inflammatory response. 11 Therefore, inhibition of renin provides an attractive option for inhibiting the RAAS at its origin. 20 In the present study, aliskiren was able to attenuate the amount of exudate and granuloma formation significantly, in a dosedependent manner, in the cotton-induced granuloma model of inflammation in rats and successfully inhibit paw edema formation in formalin-induced paw edema formation in rats.…”

“…10 Aliskiren has been shown to be able to significantly reduce gingival inflammation and enhance wound-healing processes. 11 Another study proved its analgesic and anti-allodynic activity in animal models of pain. 12 These studies demonstrate that aliskiren is a good candidate to be tested for its anti-inflammatory effects.…”