Red complex bacteria have been demonstrated to be the predominant microbial species involved in PD progression; among them, P. gingivalis is regarded as a keystone pathogen in adult periodontitis (Hajishengallis et al., 2012; Maekawa et al., 2014). It is a common bacterium in the oral microbiome and a successful colonizer of oral epithelial cells (Lamont et al., 2018). The virulence factors of P. gingivalis, including fimbriae proteins, lipopolysaccharide (LPS) and gingipains, play important roles in pathogen interactions and inflammation. P. gingivalis fimbriae (FimA), a filamentous structure identified on the surfaces of these bacteria, play a role in the invasion and colonization of host tissues (Dashper et al., 2017). P. gingivalis FimA is also closely associated with bacterial adhesion and biofilm formation (Dashper et al., 2017); they may affect the kidney by activating adhesion signals, phagocytosis, inflammatory response, and inducible nitric oxide synthase (iNOS). Inflammation that fails to clear the pathogen can be characterized as non-productive when the infection becomes chronic. With these two chronic diseases, long-term exposure to various byproducts of the disease and complications related to disruptions in homeostasis can lead to distal effects in a variety of body functions and sites.

P. gingivalis activates adhesion signals by stimulating macrophages and neutrophils. Complement receptor 3 (CR3) can use this pathway to enhance the interaction between FimA and CR3 on the cell surface. Activated CR3 interacts with gingival flora to reduce IL-12p70. IL-12p70 production by macrophages activates T cells and NK cells to produce IFN-γ, which in turn activates the bactericidal function of macrophages (Trinchieri, 2003). Therefore, CR3 blockade may represent a promising immunomodulatory approach for controlling human periodontitis and associated systemic diseases (Cai et al., 2019). P. gingivalis FimA can activate the interaction of CXC-chemokine receptor 4 (CXCR4) and TLR2 in macrophages and induce cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signaling. However, they can inactivate glycogen synthase kinase-3β (GSK3β) and disrupt iNOS-dependent phagocytosis of macrophages. P. gingivalis FimA activate TLR2/TLR1 on macrophages and induce the production of a small amount of cAMP. Moreover, the continuous increase in cAMP activates PKA in macrophages and destroys the bactericidal function of iNOS, which is dependent on NF-κB (Wang et al., 2010). This indicates that phagocytosis by macrophages may induce kidney injury. In addition, the elevation of cAMP leads to a decrease in the production of nitric oxide (NO) by renal endothelial cells. The lack of NO can lead to severe renal fibrosis and enhance the interaction between neutrophils and endothelial cells (Herrera et al., 2011). The regulatory action of the cAMP/PKA pathway on cell activity depends mainly on the binding of phosphorylated cAMP response element binding protein (CREB) to the nuclear coactivator CREB binding protein (CBP) (Dyson and Wright, 2016). Therefore, FimA may be one of the factors affecting the kidneys.

Lipopolysaccharide is a component of the cell wall of Gram-negative bacteria and plays an important role in the activation of the inflammatory response in chronic periodontitis (Golz et al., 2014; Holden et al., 2014). P. gingivalis LPS may induce diabetic renal inflammation, such as glomerulosclerosis and tubulitis with infiltration of Mac-1/podoplanin-positive macrophages, via glomerular overexpression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (Kajiwara et al., 2021). In one study, mice were intraperitoneally injected with P. gingivalis LPS at a concentration of 5 mg/kg every 3 days for 1 month. Microarray analysis showed that the 10 genes with the highest expression levels in the kidney were stimulated with P. gingivalis LPS. Among them, five genes (Saa3, Ticam2, Reg3b, Ocxt2a, and Xcr1) are known to function. Mouse primary kidney glomerular endothelial cells (KEC) were cultured with or without P. gingivalis LPS. The expression levels of Saa3, Ticam2, Reg3b, Oxct21, and Xcr1 significantly increased in the 1000 ng/mL P. gingivalis LPS groups compared with the controls. when compared with the controls. In addition, upregulation of the expression levels of Saa3, Ticam2, Reg3b, Ocxt2a, and Xcr1 may be related to CKD pathogenesis. The five overexpressed genes in the kidney-derived endothelial cells were induced by LPS (Harada et al., 2018). Each of these five genes has its own role. Saa3 expression levels have been utilized to ascertain the number of infiltrated macrophages during chronic inflammation in obese adipose tissue (Sanada et al., 2016). Mal/Toll/IL-1R (TIR) domain-containing adaptor molecule 2 (Ticam2), also known as TRAM (TRIF-related adaptor molecule), acts as a sorting adaptor on the early endosomes for the recruitment of TIR-containing adapter molecule (TICAM)-1 to TLR4, which is known to recognize LPS (Klein et al., 2015). Reg3b regulates important biological processes such as immune responses, cell adhesion, and protection via apoptosis (Ferreira et al., 2011). Increased Oxct2 expression may be related to diabetic CKD (Harada et al., 2018). Both dendritic and endothelial cells may contribute to the overexpression of Xcr1 in the kidneys (Lei and Takahama, 2012). These findings demonstrate that P. gingivalis LPS may have an effect on the kidneys.

P. gingivalis LPS can also affect the kidneys through M1 and M2 macrophages. One study indicated that P. gingivalis LPS activated M1 and M2 macrophages mainly via TLR2; this was accompanied by the observation that high concentrations of LPS produced NO by stimulating M1 macrophages, while low concentrations primarily increased cytokine expression (Holden et al., 2014). Another study showed that LPS administration promoted urinary protein production, accumulation of type I collagen in the glomeruli, and increased interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) expression in the renal cortex of the glomeruli of diabetic mice (Chou et al., 2005). It is believed that P. gingivalis LPS is involved in inducing the production of proinflammatory cytokines such as TNF-α and IL-6 in glomerular endothelial cells by binding to TLR2 and TLR4, as well as the production of anti - inflammatory cytokines such as TGF-β to promote glomerular sclerosis (Sawa et al., 2014). The initial inflammatory response of macrophages to P. gingivalis was mainly dependent on myeloid differentiation primary response 88 (MyD88), which requires synergistic TLR2 and TLR4 signaling. Although both TLR2 and TLR4 are involved in TNF-α production in macrophages, P. gingivalis preferentially exploits TLR2 in endotoxin-tolerant bone marrow-derived macrophages (BMDMs) to trigger excessive TNF-α production (Cai et al., 2019). P. gingivalis FimA inhibit the ability to stimulate IL-8 production in endothelial cells, leading to local chemokine paralysis and an uncontrolled immune response, resulting in renal dysfunction (Cai et al., 2019). Thus, P. gingivalis LPS induces the expression of TLR4 and inflammatory cytokines and activates the NF-κB signaling pathway (Kim et al., 2018).

P. gingivalis LPS also upregulates the expression and release (shedding) of the surface-bound trigger receptor on myeloid cells 1 (TREM-1) into a soluble form (sTREM-1). TREM-1 is a cell surface receptor expressed in innate immune cells. TREM-1 has synergistic effects with cell surface pattern recognition receptors (PRRs) such as toll-like- and NOD-like- receptors to accelerate the production of proinflammatory cytokines such as TNF-α and IL-1β. Peptidoglycan recognition protein 1 (PGLYRP1) is a secreted antibacterial protein that acts against Gram-positive and -negative bacteria. The components of periodontal bacteria do not bind to TREM-1 directly, but instead bind the PGLYRP1 ligand. In periodontitis patients with renal diseases, the correlation between sTREM-1 and PGLYRP1 has been shown to be positively correlated with PGLYRP1 and proinflammatory cytokines in patients with CKD before dialysis (Bostanci et al., 2013; Nylund et al., 2018).

Some virulence factors are known to be involved in the pathogenicity of P. gingivalis, including fimbriae and LPS; however, the major virulence factor is a family of cysteine proteases called gingipains. Gingipains are proteinases that are secreted by P. gingivalis and are involved in a variety of functions, including the acquisition of essential nutrients, invasion of host tissues, inactivation of cytokines and their receptors, and attenuation of neutrophil antibacterial activities. Thus, they are necessary for the survival of P. gingivalis in the anaerobic host environment (Guo et al., 2010; Bostanci and Belibasakis, 2012). Gingipains cause kidney damage by activating an inflammatory response in various immune cells, including neutrophils, macrophages, and T cells.

In vitro experiments have shown that gingipains of P. gingivalis stimulate TLR2-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. They then stimulate activated neutrophils to produce the proinflammatory cytokine TNF-α, thereby prolonging the maturation and survival time of host cells (Makkawi et al., 2017). P. gingivalis-specific gingipains can decompose the fifth complement component (C5) into C5a (fragment of complement protein C5) and C5b in two ways: directly exerting the transforming activity of C5, and activating thrombin to activate prothrombin to replace the C5 transforming enzyme (Hajishengallis et al., 2013). More importantly, recent studies have discovered an important mechanism of combined action between the C5a receptor (C5aR) and TLR2 in macrophages to promote the adaptability of P. gingivalis (Wang et al., 2010). Gingipains can directly induce the expression of CD69 and CD25 on T cells and induce IL-17 production (Yun et al., 2007). Taken together, these studies demonstrate that gingipains can adversely affect the kidneys.

A. actinomycetemcomitans is an exogenous oral bacterium associated with aggressive forms of periodontitis. This organism possesses a large number of virulence factors with a wide range of activities that enable it to colonize the oral cavity, invade periodontal tissues, evade host defenses, initiate connective tissue destruction, and interfere with tissue repair (Raja et al., 2014). More recently, renal lesions caused by other pathogens were found to be positive for the same molecular marker. A study reported the case of a 64-year-old man who experienced repeated fever for several months and presented with progressively deteriorating renal function. He had previously undergone aortic valve replacement. A. actinomycetemcomitans, a component of the oral flora, was found in the blood culture of this patient. Renal biopsy revealed diffuse proliferative glomerulonephritis (Komaru et al., 2018). This is the first report of nephritis-associated plasmin receptor (NAPlr) positivity in the glomeruli after systemic infection with A. actinomycetemcomitans. A. actinomycetemcomitans acts primarily on the kidney through PGN, outer membrane vesicles (OMVs), cytolethal distending toxin (CDT), and leukotoxin (LtxA).

Similar to LPS, the bacterial wall of oral bacteria (PGN) can stimulate blood cells to produce cytokines. PGN-associated lipoproteins can activate macrophages to produce IL-6, IL-1β, and TNF-α by binding to TLR2 receptors (Ihalin et al., 2018). LPS and PGN are prototypical classes of pathogen-associated molecular patterns (PAMPs) that are recognized by TLRs, leading to the activation of proinflammatory signaling pathways (Kawai and Akira, 2011). Together with IL-1, TNF-α activates NF-κB, which promotes the expression of apoptotic genes in nephritis and activates cell proliferation and differentiation, as well as permanent cell damage in the kidneys.

A. actinomycetemcomitans can extend their pathogenicity by releasing membrane vesicles (MVs), which represent a very basic and relevant mode of protein export from bacteria that has been referred to as ‘Type Zero’ secretion (Rompikuntal et al., 2015). There is evidence supporting that OMV internalization is a prerequisite for the induction of a proinflammatory response (Bielig et al., 2011). Moreover, colocalization analysis revealed that internalized OMVs colocalized with the endoplasmic reticulum and carried antigens, as detected using an antibody specific to whole A. actinomycetemcomitans serotype A cells. Consistent with the fact that the internalization of A. actinomycetemcomitans OMVs mediates intracellular antigen exposure, the vesicles acted as strong inducers of the cytoplasmic PGN sensor NOD1- and NOD2-dependent NF-κB activation (Thay et al., 2014). Thus, A. actinomycetemcomitans OMVs may cause a proinflammatory response in the kidneys.

A. actinomycetemcomitans is the only oral species that is known to express CDT. An estimated 66–86% of its strains express CDT, and its presence has been associated with the occurrence of PD (Fais et al., 2016). Cells of the immune system are also highly susceptible to the cell cycle arrest and apoptotic action caused by CDT, as has been demonstrated in human T cells (Shenker et al., 1999), B cells (Sato et al., 2002), and mononuclear cells (Akifusa et al., 2001). A. actinomycetemcomitans produces an immunosuppressive factor (ISF) capable of impairing human lymphocyte function by perturbing cell cycle progression. ISF is the product of the CDTB gene, one of the three genes encoding the CDT family (Shenker et al., 1999). CDT from A. actinomycetemcomitans induces cell distension and G2 cell cycle arrest in HeLa and B cell hybridoma cells. CDT-induced p21 ^CIP1/WAF1 promotes G2 cell cycle arrest in several types of mammalian cells, such as B-lineage cells and fibroblast-like cells. A. actinomycetemcomitans has been associated with periodontitis and systemic infections in humans (Sato et al., 2002). An experimental protocol was used to determine whether recombinant CDT proteins were able to induce cytokine production in human PBMCs. Individual CDT proteins are able to induce IL-1β, IL-6, and IL-8 synthesis by PBMCs (Bielig et al., 2011); furthermore, CDT-mediated increases in extracellular ATP and ATP-induced P2X₇ activation likely contribute to NOD-like receptor family pyrin domain containing 3 (NLRP3) assembly and activation. Furthermore, treating lymphocytes with CDT leads to perturbations in PI3K signaling, including phosphatidylinositol-3,4,5-triphosphate (PIP3) depletion, and decreases both Akt and GSK3β phosphorylation. In addition, CDT treatment decreases kinase activity in Akt but increases GSK3β. A. actinomycetemcomitans CDT activates the NLRP3 inflammasome in human macrophages, leading to the release of proinflammatory cytokines (Shenker et al., 2015). Therefore, we infer that A. actinomycetemcomitans may affect the kidneys by acting on immune cells.

LtxA is an important protein toxin of A. actinomycetemcomitans. LtxA affects the kidney mainly by acting on white blood cells to produce an immune response. Lymphocyte function-associated antigen 1 (LFA-1) is expressed in all white blood cells (Miller et al., 1986), and LtxA of A. actinomycetemcomitans affects different leukocyte populations (Johansson, 2011). A region of LtxA contains a series of 14 tandemly repeated amino acid sequences in the repeat region of the toxin and is shown to be responsible for receptor binding to LFA-1 (Hirschfeld et al., 2016). LtxA activates neutrophil degranulation, causing a massive release of lysosomal enzymes, net-like structures, and matrix metalloproteinases (MMPs) and induces apoptosis in lymphocytes (Hirschfeld et al., 2016). However, pretreatment of cells with a PI3K inhibitor significantly inhibited LtxA-mediated killing (DiFranco et al., 2012), suggesting that LtxA of A. actinomycetemcomitans can affect the kidneys through the PI3K pathway.

In addition to P. gingivalis and A. actinomycetemcomitans, oral microbiota may adversely affect the kidneys. F. nucleatum includes five subspecies: polymorphum, nucleatum, vincentii, fusiforme, and animalis (Dzink et al., 1990). In a previous study, P. gingivalis, T. denticola, T. forsythia, and F. nucleatum were associated with innate immune signaling and induction of periodontitis and atherosclerosis in a mouse model (Chukkapalli et al., 2018). An important factor in T. forsythia virulence is the serine proteinase inhibitor (serpin) protein, which is known as miropin. This protein inhibits serine proteases from neutrophils, thus protecting the bacteria against the proteolytic effects of neutrophils (Ksiazek et al., 2015). This suggests that these oral bacteria may elicit immune responses to the body, which may affect the kidneys. Atherosclerotic plaque progression was markedly reduced in infected TLR2^–/–TLR4^–/– mice or heterozygous mice, indicating a profound effect on plaque growth. However, bacterial genomic DNA was detected in multiple organs in TLR2^–/–TLR4^–/– mice, indicating intravascular dissemination from gingival tissue to the heart, aorta, kidney, and lungs. In addition, P. gingivalis, T. denticola, and F. nucleatum genomic DNA were also positive in the kidney, but the bacteria were not identified (Chukkapalli et al., 2018). These studies show that some oral bacteria can adversely affect the kidneys.

Among these bacteria, F. nucleatum is the oral pathogen that is most commonly found at sites of systemic infection. In a previous study, ApoE^null mice (n = 23) were orally infected with F. nucleatum subsp. vincentii ATCC 49256. The mice developed bacteremia symptoms, with F. vincentii genomic DNA detected in systemic organs (heart, aorta, kidney, liver, and lung) (Velsko et al., 2015). F. nucleatum lipid A is a hexa-acylated fatty acid that is composed of tetradecanoate (C14) and hexadecanoate (C16) and is structurally similar to Escherichia coli lipid A. This structural similarity may explain the strong activity of F. nucleatum via TLR4 (Asai et al., 2007). Furthermore, the same study showed that TLR2/TLR4 and MyD88 are required for the best activation of NF-κB and mitogen-activated protein kinases [MAPKs, including p38, extracellular signal-regulated kinase (ERK), and Jun N-terminal protein kinase (JNK)] in response to F. nucleatum (Park et al., 2014). In gingival epithelial cells (GECs), F. nucleatum infection was sufficient to induce caspase-1 activation in an NLRP3-dependent manner and the secretion of the danger signals ASC and high-mobility group box 1 protein (HMGB1) (Bui et al., 2016). Caspases are endoproteases that cleave peptide bonds in a cysteine-dependent and -directed manner. Caspases can cause cell death (pyroptosis) and inflammation (McIlwain et al., 2015). The active invader species F. nucleatum can independently invade host cells in part using extracellular adhesin and invasion molecules, such as Fusobacterium adhesion (FadA) (Xu et al., 2007; Ikegami et al., 2009). It has been reported that F. nucleatum FadA binds to E-cadherin, thus activating β-catenin signaling and differentially regulating inflammatory and oncogenic responses (Rubinstein et al., 2013). Moreover, significantly redundant FadA paralogs could contribute to severe mucosal inflammation (Sekizuka et al., 2017). Taken together, cell death and inflammation also play important roles in the kidneys.

Cytokines such as IL-1, IL-6, IL-8, IL-17, and TNF-α are associated with periodontitis and kidney disease (Figure 2). The IL-1 gene encodes inflammatory mediators involved in the pathogenesis of periodontitis and CKD (Braosi et al., 2012). In patients with CKD, it was found that plasma concentrations of IL-6 and TNF-α appeared to be more sensitive markers of odontogenic inflammation in CKD patients (Niedzielska et al., 2014). In another study, there was a positive correlation between clinical indicators and TNF-α and IL-8 levels in gingival crevicular fluid (GCF) extracted from HD patients. The levels of TNF-α and IL-8 in the GCF of HD patients were significantly higher than those in the healthy group (Dag et al., 2010).

The production of IL-1β, IL-8, and TNF-α can be induced by stimulating neutrophils in the blood through the LPS of periodontal pathogens (Yoshimura et al., 1997). IL-1 and IL-6 can be produced by stimulating peripheral blood mononuclear cells through pathogenic bacteria that express CDT (Yoshimura et al., 1997). According to a previous study, the soluble delivery of active TNF leptin (LEP) in macrophages can be achieved through the role of pathogenic proteases (Bryzek et al., 2014). IL-6, TGF-β, IL-1, and IL-21 induce the differentiation of mouse and human CD4(+) T cells into T-helper 17 (Th17) cells (Turner et al., 2010). Chronic inflammation in periodontal tissues stimulates Th17 cells to produce IL-17 (Moutsopoulos et al., 2012). IL-17 can enter the serum of patients, and studies have shown that the serum IL-17 levels of the patients were higher than those of the healthy group (Schenkein et al., 2010). Based on the above studies, we hypothesized that the pathogenic oral bacteria’s established by the periodontitis mentioned above might cause the release of cytokines by immune cells in the blood, thereby causing kidney damage.

IL-6 further increases renal inflammation by recruiting more neutrophils into the damaged kidneys and aggravates acute renal failure in ischemic mice (Kielar et al., 2005). IL-8 is a harmful chemokine involved in renal damage in glomerulonephritis and is generally associated with neutrophil accumulation and neutrophil-dependent edema at sites of acute and chronic inflammation (Niemir et al., 2004). TNF-α is involved in the progression of renal insufficiency through its cytotoxic and proinflammatory effects, such as by inducing endothelial cells (ECs) to express intercellular adhesion molecule-1 (ICAM)-1 (Izawa-Ishizawa et al., 2012). Chronically elevated circulating IL-17A levels can activate the immune response and damage the kidney tissue. IL-17A promotes upregulation of genes related to proinflammatory factors, such as IL-23 mRNA. IL-17A also increases the production of monocyte chemotactic protein-1 (MCP-1) in renal tubular epithelial cells. MCP-1 is a key driver of renal inflammatory cell aggregation and has been proposed as a biomarker for kidney damage (Orejudo et al., 2019). IL-17A can aggravate kidney inflammatory diseases such as diabetic nephropathy, hypertension, and lupus nephritis (Lavoz et al., 2019; Orejudo et al., 2019; Zhang and Li, 2020). DNA was obtained from oral mucosal cells, and IL1AC889T, IL1BC511T, IL1BC3954T, and IL1RN (intron 2) polymorphisms were analyzed by PCR-RFLP (Braosi et al., 2012). It was found that the IL1RN^∗1 allele was associated with an almost fourfold increase in risk of developing CKD. The IL1RN^∗2 allele was associated with a threefold increase in risk of PD in CKD patients. CKD in PD patients was associated with allele T for polymorphism IL1B + 3954. IL1 may be related to the gene clustering polymorphisms in PD and CKD (Schreiber et al., 2012). Cytokines may be a pathway through which periodontitis causes kidney disease; however, more research is needed.

The levels of various APPs in GCF, such as C-reactive protein (CRP), PTX family protein, fibrin, and haptoglobin, are affected by the local periodontitis response. The increase in APP concentration in plasma promotes the production of proteolytic enzymes in the body, resulting in renal endothelial cell damage, endothelial cell permeability increase, glomerular filtration dysfunction, and ultimately aggravate kidney disease, which is often considered to be an important bridge between periodontitis and systemic inflammation.

A study on the effects of non-surgical periodontal treatment on serum CRP levels found that systemic inflammation in patients with CKD resulted from periodontitis (Yazdi et al., 2013). Periodontitis treatment can reduce serum CRP levels in patients with CKD. In 2011, a study found that the average serum CRP levels in 50 periodontitis patients were significantly higher than in healthy controls. Patients with severe periodontitis generally have a high level of clinical attachment loss, and the mean CRP level is higher in patients with moderate periodontitis (Pejcic et al., 2011). CRP can combine C1q and complement factors by activating the classical and alternative complement pathways. It can induce thrombus formation by activating white blood cells, inducing cytokine release and monocyte aggregation, and inducing platelet aggregation. CRP also damages the endothelial cells of the kidney, promotes atherosclerotic plaque formation in arteries, and results in renal artery occlusion, poor blood circulation, and aggravation of kidney disease (Melnikov et al., 2020).

Pentraxins (PTXs) are classical APPs that have been known for over a century. They are typical signs of acute phase response and emerging biomarkers of inflammation that can modulate and play key roles in the immune inflammatory response. The prototype protein of the long-entrain group is pentraxins 3 (PTX3). PTX3, which is associated with CKD and periodontitis, is a truly independent indicator of disease activity. PTX3 amplifies the inflammatory process by binding to the C1q component of the complement cascade (Pradeep et al., 2012). In different cell types, such as endothelial phagocytes, smooth muscle cells, fibroblasts, and glial cells, TNF-α and ILs upregulate PTX3 transcription and are involved in atherogenesis. A 2011 study on the relationship between plasma PTX3 and CKD suggested that neutrophils and monocytes accumulate at the lesion site and that cytokines such as TNF-α, IL-1, and IL-6 are amplified (Pradeep et al., 2012). Furthermore, PTX3 is highly expressed in periodontitis; after experimental induction of periodontitis, serum PTX3 levels were significantly increased 24 h after injection and continued to increase for 21 days (Leira et al., 2020). When periodontal inflammation occurs, lymphocytes and monocytes in the blood are activated and proliferate. Monocytes and T cells release IL-1 and TNF-α in renal tubules and promote PTX3 mRNA expression in renal tubular epithelial cells. Increased PTX3 production can also be jointly activated by IL-1 and CD40L, as shown in renal tubular epithelial cells (Nauta et al., 2005). PTX3 can aggravate kidney disease during inflammation, with (Valente et al., 2019) studies showing that decreased renal function may be associated with higher PTX3 levels in patients with CKD (Sjoberg et al., 2016). PTX3 can increase the expression of endothelial tissue factors and participate in the formation of thrombosis and vascular ischemia of tissue factors by endothelial cells (Napoleone et al., 2002). PTX3 promotes the production of platelet activating factor and proinflammatory mediators in mesangial cells, which can cause platelets to adhere to renal tissue and cause damage (Bussolati et al., 2003).

Asymmetric dimethyl arginine is used to assess endothelial function and is the most effective endogenous inhibitor of nitric oxide synthase (NOS). NOS is a key regulator of vascular tension and plays a key role in endothelial dysfunction, atherosclerosis progression, and cardiovascular disease (Oliva-Damaso et al., 2019). Endothelial dysfunction is related to periodontitis, and pathogenic bacteria or products of PD can directly affect endothelial function (Gurav, 2014). These pathogens trigger an inflammatory response throughout the body, which can have harmful effects on the blood vessel walls (Gurav, 2014). The presence of NOS and cyclooxygenase (COX) isozymes were measured in mice killed 7 days after unilateral periodontitis induction, and COX and NOS gene expression in the aorta was analyzed by real-time polymerase chain reaction (RT-PCR) (Campi et al., 2016). Consistent with previous findings, the expression of endothelial nitric oxide synthase (eNOS) in mice decreased and the expression of iNOS and COX-2 increased. This suggests that ligative periodontitis causes endothelial dysfunction in mice. Renal endothelial injury may be a pathway for periodontal pathogens that cause other diseases (Grubbs et al., 2017). A study linking CKD with endothelial dysfunction and periodontitis assessed the effect of periodontal therapy on renal function in patients with CKD in the short term. The results showed a significant decrease in ADMA levels after periodontal treatment, which may indicate improved endothelial function and a better prognosis for CKD development (Almeida et al., 2017). Therefore, periodontitis can lead to elevated ADMA levels, resulting in renal endothelial dysfunction.

Matrix metalloproteinases are found in the periodontium and are calcium-dependent zinc-containing proteolytic enzymes that are responsible for organ oogenesis, normal tissue turnover, and tissue breakdown (Nylund et al., 2015). Neutrophils are the main source of matrix metalloproteinase 8 (MMP8). Studies on the content of MMP8 in saliva have suggested that periodontal inflammation triggers systemic diseases, including CKD (Nylund et al., 2015). Periodontal bacteria stimulate immune cells to release MMP8 into the bloodstream, and studies have shown that serum MMP8 levels are higher in patients with generalized and invasive periodontitis (Nizam et al., 2014). Oral bacteria such as F. nucleatum, P. gingivalis and T. denticola can induce the release and activation of MMP8 by neutrophils (Ding et al., 1997). A. actinomycetemcomitans leukotoxin reportedly affects different white blood cell populations and activates neutrophils to degranulate, resulting in lysosomal enzymatic reticular structure and matrix proteinase (Ding et al., 1997). MMP family performs various functions in the kidneys. MMPs, which are collectively responsible for maintaining extracellular matrix (ECM) protein scaffolds around the body, are involved in renal fibrosis and chronic remodeling, diabetic nephropathy, polycystic kidney disease, and glomerulonephritis. MMPs may also be involved in the regulation of renal inflammation (Basu et al., 2015). MMP8 and its various molecular subtypes have been found in the urine of diabetic nephropathy patients, and MMP8 reportedly plays an important role in the pathogenesis of diabetic nephropathy. MMP8 may also mediate tissue destruction by lysing collagen and protease inhibitors (serpins) (Nylund et al., 2015). There is a large amount of evidence suggesting that MMPs are associated with both periodontitis and kidney disease; however, the suggestion that MMPs may be a “bridge” that mediates periodontitis to cause kidney disease still needs further confirmation.