*2.3. Oxidative Stress*

Reactive oxygen species (ROS) are an important primary defense factor in periodontal disease [40]. ROS are produced by inflammatory cells such as polymorphonuclear leukocytes and vascular smooth muscle cells, and nicotine adenine dinucleotide phosphate oxidase is a major source of ROS generation. However, although the main target of ROS is nuclear DNA, excessive ROS production will generate lipid peroxide through homeostasis of oxidative balance in tissues, and lipid peroxide in local periodontal lesions is associated with periodontal diseases [41]. Moreover, ROS are associated with oxidative stress and long-lasting systemic oxidative stress, which is thought to cause multi-organ failure [42]. Reactive nitrogen intermediates are also important in oxidative stress. For example, peroxynitrite, which is produced by nitric oxide and superoxide anion causes endothelial damage [43]. There are several oxidative stress markers such as malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and 4-hydroxy-2-nonenal (4-HNE). It is plausible that oxidative stress has a significant impact on local periodontal lesions, and the e ffects of oxidative stress on the systemic inflammation have been shown by several research groups. For example, tissue 8-OHdG levels increased in multiple organs, such as the liver, heart, kidneys, and brain in a periodontal inflammation model [41]. Furthermore, in saliva, MDA and 8-OHdG levels are thought to be associated with oxidative periodontal lesions, and 4-HNE levels in the saliva may reflect systemic inflammation [44]. Conversely, there has been a report indicating that nuclear factor erythroid 2-related factor (NrF2), which is a key regulator of antioxidants, plays an important role in protecting against tissue destruction in periodontitis [45]. Thus, the balance between oxidative stress and antioxidants is speculated to be associated with occurrence, severity, and progression of periodontal disease.

### *2.4. Inflammatory Reaction and Endothelial Dysfunction*

One of the most important mechanisms in systemic organ dysfunction in periodontal disease is due to endothelial dysfunction, which is associated with platelet aggregation, foam-cell formation, and development of atheroma [46]. In CKD, proteinuria is one of the most important surrogate markers of kidney prognosis and reflects endothelial dysfunction [34]. As stated above, inflammatory cytokines originating from bacteremia or paracrine from distal periodontal lesions will cause vascular permeability and vascular wall injury [32]. In addition to inflammatory cytokines, endothelial adhesion molecules, such as ICAM-1 and VCAM-1, play an important role in vascular injury via the activation of endothelial cells and smooth muscle cell proliferation [47]. Endothelial injury will cause arterial stenosis, resulting in hypertension [47].

In addition to the above observations, an animal model showed that ridocaine inhibited endothelial dysfunction of the systematic artery in rats with periodontal inflammation and decreased ROS was associated with such a mechanism [48]. Furthermore, investigation in patients with chronic periodontitis demonstrated that endothelial dysfunction of the branchial artery occurred with greater frequency in patients with periodontitis than in those without periodontitis [46]. Interestingly, this study and other investigators showed that together with various cytokines and inflammation-related molecules, oxidative stress regulated the relationship between periodontitis and endothelial dysfunction [49,50].

### *2.5. Matrix Metalloproteinases and Transglutaminases*

When discussing the pathological mechanisms and development of periodontal disease, information regarding gingival remodeling and healing steps is important. In addition, an understanding of the protective system of oral tissues from microbial challenge in periodontal disease is also essential. From this standpoint, there is an interesting study that focused on the pathological roles of matrix metalloproteinase (MMP) and transglutaminases in patients with chronic periodontitis [51]. In short, when MMP-2 and -9 and transglutaminase-1–3 were analyzed in 22 patients with chronic periodontitis and healthy controls, transglutaminase-1 and 3 mRNA levels in chronic periodontitis patients were lower than those in healthy controls [51]. Finally, this study showed that di fferent transglutaminases might regulate gingival remodeling/healing and adaptive processes in patients with chronic periodontitis. Conversely, it has also been reported that transglutaminase-2 may play an important role in vascular calcification in CKD [52]. Thus, the pathological roles of transglutaminases in CKD are not fully understood.

### **3. Periodontal Disease and Chronic Kidney Disease**

### *3.1. Impact on Periodontal Disease from other Pathological Conditions*

As discussed above, there is evidence suggesting that there is a direct relationship between the inflammation of periodontal disease and CKD, and renal function may decline for various reasons. CKD may evolve from any chronic renal disorder etiology, and typically includes diabetes, hypertension, and chronic nephritis [1,4]. In contrast, periodontal diseases can cause dysfunction of various organs, such as the heart, liver, and kidney. Therefore, the reduction in renal function due to the burden of other diseases as a result of periodontal disease should be considered.
