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Functional Local Renin-Angiotensin System in Human and Rat Periodontal Tissue.

Santos CF, Morandini AC, Dionísio TJ, Faria FA, Lima MC, Figueiredo CM, Colombini-Ishikiriama BL, Sipert CR, Maciel RP, Akashi AP, Souza GP, Garlet GP, Rodini CO, Amaral SL, Becari C, Salgado MC, Oliveira EB, Matus I, Didier DN, Greene AS - PLoS ONE (2015)

Bottom Line: However, in inflamed tissue the immunoreactivity was greater for the AT1R compared to AT2R in fibroblasts.Ang 1-7 formation was significantly greater when human gingiva homogenates were incubated with chymostatin alone compared to incubation without any inhibitor, only captopril, or captopril and chymostatin.Furthermore, blocking AT1R and renin can significantly prevent periodontal bone loss induced by EP in rats.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil.

ABSTRACT
The initiation or progression of periodontitis might involve a local renin-angiotensin system (RAS) in periodontal tissue. The aim of this study was to further characterize the local RAS in human and rat periodontal tissues between healthy and periodontally-affected tissue. Components of the RAS were investigated using in vitro, ex vivo and in vivo experiments involving both human and Wistar rat periodontium. Although not upregulated when challenged with P. gingivalis-lipopolysaccharide, human gingival and periodontal ligament fibroblasts expressed RAS components. Likewise, healthy and inflamed human gingiva expressed RAS components, some of which were shown to be functional, yet no differences in expression were found between healthy and diseased gingiva. However, in inflamed tissue the immunoreactivity was greater for the AT1R compared to AT2R in fibroblasts. When compared to healthy tissue, ACE activity was increased in human gingiva from volunteers with gingivitis. Human-gingiva homogenates generated Ang II, Ang 1-9 and Ang 1-7 when incubated with precursors. In gingiva homogenates, Ang II formation from Ang I was nearly abolished only when captopril and chymostatin were combined. Ang 1-7 formation was significantly greater when human gingiva homogenates were incubated with chymostatin alone compared to incubation without any inhibitor, only captopril, or captopril and chymostatin. In rat gingiva, RAS components were also found; their expression was not different between healthy and experimentally induced periodontitis (EP) groups. However, renin inhibition (aliskiren) and an AT1R antagonist (losartan) significantly blocked EP-alveolar-bone loss in rats. Collectively, these data are consistent with the hypothesis that a local RAS system is not only present but is also functional in both human and rat periodontal tissue. Furthermore, blocking AT1R and renin can significantly prevent periodontal bone loss induced by EP in rats.

No MeSH data available.


Related in: MedlinePlus

Scheme of Possible Mechanisms of the Renin-Angiotensin System (RAS) in Periodontal Tissue.1) Periodontal pathogens induce a host-pro-inflammatory response which can affect the RANK-RANKL-OPG axis in bone metabolism. RANKL/OPG balance is an important factor for regulating bone resorption in the periodontal environment. Osteoclast differentiation and activation are driven by the interaction of RANK (receptor activator of nuclear factor-кB) with its ligand, RANKL. Osteoprotegerin (OPG) is a decoy receptor for RANKL that inhibits RANK-RANKL engagement, as previously reviewed by Graves et al. (2011) [70]. 2) AT1R and AT2R are present in periodontal tissue, including periodontal fibroblasts. Ang I is generated from angiotensinogen (AGT) by renin. Ang II generated from Ang I (by ACE) acts via the AT1R to induce the activation of the ERK pathway which in turn can upregulate the expression of RANKL in osteoblasts leading to a variety of cellular outcomes [60,67] and possibly enhancing bone resorption. 3) Ang II formation decreased when human gingiva homogenates were incubated with both captopril (ACE inhibitor) and chymostatin. After 14 days of experimentally-induced periodontitis, renin inhibition by treatment with aliskiren or an AT1R antagonist (e.g. losartan) significantly attenuated bone resorption (4), probably decreasing activation of AT1R downstream pathway.
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pone.0134601.g007: Scheme of Possible Mechanisms of the Renin-Angiotensin System (RAS) in Periodontal Tissue.1) Periodontal pathogens induce a host-pro-inflammatory response which can affect the RANK-RANKL-OPG axis in bone metabolism. RANKL/OPG balance is an important factor for regulating bone resorption in the periodontal environment. Osteoclast differentiation and activation are driven by the interaction of RANK (receptor activator of nuclear factor-кB) with its ligand, RANKL. Osteoprotegerin (OPG) is a decoy receptor for RANKL that inhibits RANK-RANKL engagement, as previously reviewed by Graves et al. (2011) [70]. 2) AT1R and AT2R are present in periodontal tissue, including periodontal fibroblasts. Ang I is generated from angiotensinogen (AGT) by renin. Ang II generated from Ang I (by ACE) acts via the AT1R to induce the activation of the ERK pathway which in turn can upregulate the expression of RANKL in osteoblasts leading to a variety of cellular outcomes [60,67] and possibly enhancing bone resorption. 3) Ang II formation decreased when human gingiva homogenates were incubated with both captopril (ACE inhibitor) and chymostatin. After 14 days of experimentally-induced periodontitis, renin inhibition by treatment with aliskiren or an AT1R antagonist (e.g. losartan) significantly attenuated bone resorption (4), probably decreasing activation of AT1R downstream pathway.

Mentions: The AT1R localized on osteoblasts [60,61] may trigger reactive oxygen species (ROS), affecting RAS and subsequently extracellular-signal-regulated kinase (ERK) and P38 mitogen-activated protein kinase (p38) which both modulate NF-кB leading to various factors such as osteocalcin (OCN), alkaline phosphatase (ALP), IL-1, IL-6, TNFα, MMPs, and RANKL.[60] By inhibiting the AT1Rs on osteoblasts either directly with an AT1R antagonist (e.g. losartan) or upstream of Ang II by inhibiting the production of the Ang II precursors by blocking renin (e.g. aliskiren) thereby inhibiting the production of IL-1β, NF-кB, TNFα, ALP and ERK; crucial for osteoblasts’ production of RANKL (IL-1β,); cell differentiation of preosteoblasts into osteoblasts (TNFα); and the matrix calcification by mature osteoblasts (ALP). This possible mechanism is illustrated in Fig 7. It is important to note that this hypothesized AT1R mechanisms is not suggested to be responsible for all periodontal bone loss.


Functional Local Renin-Angiotensin System in Human and Rat Periodontal Tissue.

Santos CF, Morandini AC, Dionísio TJ, Faria FA, Lima MC, Figueiredo CM, Colombini-Ishikiriama BL, Sipert CR, Maciel RP, Akashi AP, Souza GP, Garlet GP, Rodini CO, Amaral SL, Becari C, Salgado MC, Oliveira EB, Matus I, Didier DN, Greene AS - PLoS ONE (2015)

Scheme of Possible Mechanisms of the Renin-Angiotensin System (RAS) in Periodontal Tissue.1) Periodontal pathogens induce a host-pro-inflammatory response which can affect the RANK-RANKL-OPG axis in bone metabolism. RANKL/OPG balance is an important factor for regulating bone resorption in the periodontal environment. Osteoclast differentiation and activation are driven by the interaction of RANK (receptor activator of nuclear factor-кB) with its ligand, RANKL. Osteoprotegerin (OPG) is a decoy receptor for RANKL that inhibits RANK-RANKL engagement, as previously reviewed by Graves et al. (2011) [70]. 2) AT1R and AT2R are present in periodontal tissue, including periodontal fibroblasts. Ang I is generated from angiotensinogen (AGT) by renin. Ang II generated from Ang I (by ACE) acts via the AT1R to induce the activation of the ERK pathway which in turn can upregulate the expression of RANKL in osteoblasts leading to a variety of cellular outcomes [60,67] and possibly enhancing bone resorption. 3) Ang II formation decreased when human gingiva homogenates were incubated with both captopril (ACE inhibitor) and chymostatin. After 14 days of experimentally-induced periodontitis, renin inhibition by treatment with aliskiren or an AT1R antagonist (e.g. losartan) significantly attenuated bone resorption (4), probably decreasing activation of AT1R downstream pathway.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526652&req=5

pone.0134601.g007: Scheme of Possible Mechanisms of the Renin-Angiotensin System (RAS) in Periodontal Tissue.1) Periodontal pathogens induce a host-pro-inflammatory response which can affect the RANK-RANKL-OPG axis in bone metabolism. RANKL/OPG balance is an important factor for regulating bone resorption in the periodontal environment. Osteoclast differentiation and activation are driven by the interaction of RANK (receptor activator of nuclear factor-кB) with its ligand, RANKL. Osteoprotegerin (OPG) is a decoy receptor for RANKL that inhibits RANK-RANKL engagement, as previously reviewed by Graves et al. (2011) [70]. 2) AT1R and AT2R are present in periodontal tissue, including periodontal fibroblasts. Ang I is generated from angiotensinogen (AGT) by renin. Ang II generated from Ang I (by ACE) acts via the AT1R to induce the activation of the ERK pathway which in turn can upregulate the expression of RANKL in osteoblasts leading to a variety of cellular outcomes [60,67] and possibly enhancing bone resorption. 3) Ang II formation decreased when human gingiva homogenates were incubated with both captopril (ACE inhibitor) and chymostatin. After 14 days of experimentally-induced periodontitis, renin inhibition by treatment with aliskiren or an AT1R antagonist (e.g. losartan) significantly attenuated bone resorption (4), probably decreasing activation of AT1R downstream pathway.
Mentions: The AT1R localized on osteoblasts [60,61] may trigger reactive oxygen species (ROS), affecting RAS and subsequently extracellular-signal-regulated kinase (ERK) and P38 mitogen-activated protein kinase (p38) which both modulate NF-кB leading to various factors such as osteocalcin (OCN), alkaline phosphatase (ALP), IL-1, IL-6, TNFα, MMPs, and RANKL.[60] By inhibiting the AT1Rs on osteoblasts either directly with an AT1R antagonist (e.g. losartan) or upstream of Ang II by inhibiting the production of the Ang II precursors by blocking renin (e.g. aliskiren) thereby inhibiting the production of IL-1β, NF-кB, TNFα, ALP and ERK; crucial for osteoblasts’ production of RANKL (IL-1β,); cell differentiation of preosteoblasts into osteoblasts (TNFα); and the matrix calcification by mature osteoblasts (ALP). This possible mechanism is illustrated in Fig 7. It is important to note that this hypothesized AT1R mechanisms is not suggested to be responsible for all periodontal bone loss.

Bottom Line: However, in inflamed tissue the immunoreactivity was greater for the AT1R compared to AT2R in fibroblasts.Ang 1-7 formation was significantly greater when human gingiva homogenates were incubated with chymostatin alone compared to incubation without any inhibitor, only captopril, or captopril and chymostatin.Furthermore, blocking AT1R and renin can significantly prevent periodontal bone loss induced by EP in rats.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil.

ABSTRACT
The initiation or progression of periodontitis might involve a local renin-angiotensin system (RAS) in periodontal tissue. The aim of this study was to further characterize the local RAS in human and rat periodontal tissues between healthy and periodontally-affected tissue. Components of the RAS were investigated using in vitro, ex vivo and in vivo experiments involving both human and Wistar rat periodontium. Although not upregulated when challenged with P. gingivalis-lipopolysaccharide, human gingival and periodontal ligament fibroblasts expressed RAS components. Likewise, healthy and inflamed human gingiva expressed RAS components, some of which were shown to be functional, yet no differences in expression were found between healthy and diseased gingiva. However, in inflamed tissue the immunoreactivity was greater for the AT1R compared to AT2R in fibroblasts. When compared to healthy tissue, ACE activity was increased in human gingiva from volunteers with gingivitis. Human-gingiva homogenates generated Ang II, Ang 1-9 and Ang 1-7 when incubated with precursors. In gingiva homogenates, Ang II formation from Ang I was nearly abolished only when captopril and chymostatin were combined. Ang 1-7 formation was significantly greater when human gingiva homogenates were incubated with chymostatin alone compared to incubation without any inhibitor, only captopril, or captopril and chymostatin. In rat gingiva, RAS components were also found; their expression was not different between healthy and experimentally induced periodontitis (EP) groups. However, renin inhibition (aliskiren) and an AT1R antagonist (losartan) significantly blocked EP-alveolar-bone loss in rats. Collectively, these data are consistent with the hypothesis that a local RAS system is not only present but is also functional in both human and rat periodontal tissue. Furthermore, blocking AT1R and renin can significantly prevent periodontal bone loss induced by EP in rats.

No MeSH data available.


Related in: MedlinePlus