Klotho inhibits H₂O₂‐induced oxidative stress and apoptosis in periodontal ligament stem cells by regulating UCP2 expression

Abstract

Background Periodontitis, known as a human chronic in ammatory disease, has affected the life of millions of individuals. Known risk factors such as metabolic disease and oxidative stress have been reported to be closely associated with the initiation or development of periodontitis. However, the etiology of periodontitis remains unclear. Klotho, a single-pass transmembrane protein, has been widely reported to modulate cellular processes in various diseases. However, the role of Klotho in periodontitis is unknown.Results In this study, we designed and conducted a series of experiments to evaluate the role of Klotho in chronic periodontitis. Our experimental results showed that Klotho was downregulated in the gingival tissues, gingival crevicular uid (GCF), and periodontal ligament stem cells (PDLSCs) of chronic periodontitis patients. Besides, Klotho upregulated the production of uncoupling protein 2 (UCP2) in H 2 O 2treated PDLSCs. In function, Klotho inhibited H 2 O 2 -induced oxidative stress and cellular apoptosis in PDLSCs. Moreover, the rescue assay suggested that UCP2 knock-down suppressed the effects of Klotho on H 2 O 2 -induced oxidative stress and apoptosis in PDLSCs.Conclusions In conclusion, we found that Klotho inhibits H 2 O 2 -induced oxidative stress and apoptosis in PDLSCs by regulating UCP2 expression. This novel discovery may provide a potential target for chronic periodontitis treatment.

Recombinant human klotho protects against hydrogen peroxide-mediated injury in human retinal pigment epithelial cells via the PI3K/Akt-Nrf2/HO-1 signaling pathway

“…In addition, pretreatment of ARPE-19 cells with recombinant Klotho protein suppressed ROS and MDA levels induced by H 2 O 2 , elevated antioxidant enzyme (SOD2, CAT, GPX) levels, mitochondrial membrane potential, and inhibited cell apoptosis. Previous reports on Klotho attenuating oxidative stress and apoptosis in cardiomyocytes [ 36 ], Periodontal ligament stem cells [ 37 ] and lens cells [ 38 ] are consistent with our results. It is suggested that Klotho has a protective effect on oxidative stress in ARPE-19 cells.…”

Serum α-Klotho associated with oral health among a nationally representative sample of US adults

“…Previous studies have shown that under a simulated oxidative stress circumstance by H 2 O 2 , the level of reactive oxygen species (ROS) and malondialdehyde were both reduced, meanwhile, the activity of antioxidant enzymes (including superoxide dismutase, glutathione peroxidase, and catalase) was restored, by the treatment of klotho protein in hPLSC. Moreover, the expressions of apoptotic-related proteins (including BAX and Caspase-3) in hPLSCs were also reduced by the addiction of klotho (32,40). Thus, a deficiency of klotho may attribute to the accumulation of ROS and the acceleration of cell apoptosis, leading to the deterioration of oral health eventually.…”

“…The observed association between klotho and oral health in our study was consistent with previous studies. A cross-sectional study conducted in China showed that compared with those in the healthy counterparts, the levels of klotho in the gingival crevicular fluid and gingival tissues of chronic periodontitis patients were significantly lower ( 32 ). Another cross-sectional study conducted in the US demonstrated that increased tooth pulp density was observed in a hyperphosphatemic familial tumoral calcinosis patient caused by mutations in klotho ( 33 ).…”

“…Several possible mechanisms may explain the association between klotho and oral health. First, klotho could inhibit oxidative stress and down-regulate cell apoptosis in human periodontal ligament stem cells (hPLSCs) ( 32 , 40 ), which were considered a potential mechanism underlying oral conditions ( 41 ). Previous studies have shown that under a simulated oxidative stress circumstance by H 2 O 2 , the level of reactive oxygen species (ROS) and malondialdehyde were both reduced, meanwhile, the activity of antioxidant enzymes (including superoxide dismutase, glutathione peroxidase, and catalase) was restored, by the treatment of klotho protein in hPLSC.…”

“…Given that oral health could deteriorate with senescence ( 30 , 31 ), it is crucial to determine the association between serum klotho and oral health, to provide a guide for oral condition prevention. Although abnormal histology and morphology of oral structures were observed in both human ( 32 , 33 ) and animal specimens ( 34 , 35 ), it is still unclear whether klotho is associated with oral health in a large population-based study.…”