Introduction
Chronic kidney disease (CKD) has been recognized as an important public
health problem worldwide, and the global estimated prevalence of CKD is
approximately 13.4%(Lv and Zhang 2019). The overall prevalence of CKD
is more than 10% in China, and CKD has become an important public
health problem(Wang et al. 2023). Although CKD risk factors such as
poorly controlled diabetes and hypertension are well established,
efforts to reduce these risk factors alone have not yet resulted in a
decrease in the prevalence of CKD(Coresh et al. 2007). Therefore,
identifying nontraditional modifiable risk factors for CKD has become an
important public health issue worldwide.
Periodontitis is a chronic inflammatory disease with a high prevalence
of 45%–50% and is the sixth most common human disease(Rehnqvist
1981). Almost 90% of Chinese adults suffer from periodontal disease of
various severities, and over 30% have severe periodontitis(Jiao et al.
2021). The progression of periodontitis leads to tooth loss, impaired
quality of life and significant systemic inflammation(Tonetti, Van Dyke
and Working group 1 of the joint 2013). Several studies have shown an
association between periodontitis and systemic diseases, including
diabetes mellitus(Genco and Borgnakke 2013), cardiovascular disease(Bui
et al. 2019), and CKD(Deschamps-Lenhardt, Martin-Cabezas, Hannedouche
and Huck 2019, Kapellas, Singh, Bertotti, Nascimento, Jamieson and Perio
2019). Interestingly, periodontitis and CKD share common risk factors,
such as age, smoking and poorly controlled diabetes(Fisher, Taylor,
Papapanou, Rahman and Debanne 2008). Studies have suggested a
bidirectional relationship between periodontitis and CKD based on
biological research. Macrophage polarization plays a key role in
inflammatory processes, including periodontitis and CKD(Navarrete et al.
2014). Macrophage polarization toward the M1 phenotype and activation byPorphyromonas gingivalis (P.g ) play proinflammatory roles
through the secretion of the cytokines IL-1β and IL-6 (Lew et al. 2018),
which are closely associated with the destructive phase of
periodontitis(Wang et al. 2021). An increased proportion of M1
macrophages positively correlates with progressive periodontitis(Yang et
al. 2018). More importantly, M1 macrophage polarization has been
reported to be associated with the progression of renal lesions in
animal models(Anders and Ryu 2011, Lech et al. 2014). Macrophage
polarization to the proinflammatory M1 phenotype is characterized by the
production of certain inflammatory factors (IL-1β, IL-6 and IL-17) in
damaged kidney tissue(Kon, Linton and Fazio 2011, Ricardo, van Goor and
Eddy 2008). Some data suggest that uncontrolled macrophage polarization
might be an important mechanism for the chronic inflammation observed in
CKD(Li et al. 2015) and periodontitis. Therefore, inflammatory cytokines
produced by macrophage polarization may play a role in periodontitis and
CKD.
Nuclear factor kappa B (NF-κB) is a transcription factor with numerous
biological functions, including regulating the expression of various
proinflammatory factors(Mussbacher et al. 2019). CKD is associated with
inflammation and immune responses, which activate the NF-кB signaling
pathway and upregulate the expression of many downstream factors,
including IL-6, ICAM-1 and MCP-1(Sucajtys-Szulc, Debska-Slizien,
Rutkowski, Szolkiewicz, Swierczynski and Smolenski 2022). The microbiota
plays important roles in metabolism, nutritional intake, physiology and
maturation of the immune system, and it aids the progression of
CKD(Bhargava, Merckelbach, Noels, Vohra and Jankowski 2022). Some
bacteria, including P.g , Treponema
denticola (T.d ), and Tonerella
forsythia (T.f ), were examined, and the results indicated their
role in promoting the initiation and progression of inflammation in
periodontitis and CKD(Mahendra et al. 2022). The gram-negative
bacteria P.g is one of the most important periodontal pathogens
that is frequently observed in the subgingival biofilm(Baek, Ji, Kim and
Choi 2015, Palm, Demirel, Bengtsson and Khalaf 2015). P.glipopolysaccharide (LPS) can induce periodontal diseases by increasing
the number of M1 phenotype macrophages via the NF-кB signaling
pathway(Huang, Tian, Li and Xu 2019). Moreover, M1 macrophages produce
many proinflammatory factors in response to P.gstimulation(Holden, Attard, Laughton, Mansell, O’Brien-Simpson and
Reynolds 2014, Lam, O’Brien-Simpson, Holden, Lenzo, Fong and Reynolds
2016), and these effects were associated with NF-кB pathway
activation(Liu et al. 2020). Studies have suggested that elevated serum
antibodies against P.g are associated with decreased renal
function(Iwasaki et al. 2012). More importantly, it has been shown that
LPS derived from P.g damages glomerular endothelial cells to
promote kidney disease in mice, suggesting that P.g may promote
the pathological process of CKD. NLRP3, which is the downstream
transcription factor of NF-κB signaling, is a pattern recognition
receptor with a key role in host defense against pathogens(Agostini,
Martinon, Burns, McDermott, Hawkins and Tschopp 2004, Goncalves et al.
2017). NLRP3, which consists of apoptosis-associated speck-like protein
(ASC) and caspase-1, assembles the NLRP3 inflammasome(Agostini,
Martinon, Burns, McDermott, Hawkins and Tschopp 2004), which plays key
roles in CKD and periodontitis. P.g is also considered to be a
crucial factor that modulates inflammation by activating NF-κB/NLRP3
signaling(Lv, Fan, Jiang, Wang, Qiu and Ji 2021). Therefore, we
hypothesized that P.g may promote the progression of CKD via the
NF-κB/NLRP3 signaling pathway in patients with periodontitis.
Ferroptosis is a regulatory cell death mode induced by the small
molecule erastin that is different from autophagy, apoptosis, and
necrosis(Dixon et al. 2012). Our previous study showed that P.gcould directly cause ferroptosis in the liver and trigger NAFLD in
vivo and in vitro (Yao, Lan, Li, Wang, Qi and Liu 2023).
Ferroptosis is involved in inflammatory processes in HGFs in response
to P.g products. Ferroptosis is observed in the gingival tissue
of rats with periodontitis(Qiao et al. 2022). In recent years,
ferroptosis has emerged as a major area of focus in the molecular
mechanisms of CKD. The expression of SLC7A11 (a cystine-glutamic acid
anti-transporter) reduces the level of glutathione (GSH) and leads to
ferroptosis in vascular smooth muscle cells, which regulates the
occurrence of CKD(Ye et al. 2022). Zhou et al. found that the expression
of glutathione peroxidase 4 (GPX4) in renal tubular epithelial cells was
decreased, and inhibiting iron death notably decreased renal injury and
inflammatory cell accumulation in kidney disease patients(Zhou, Xue, Hou
and Dai 2022). Moreover, the NF‑κB pathway is linked to ferroptosis;
NF‑κB p65 phosphorylation suppresses ferroptosis, and p65 deletion
contributes to intestinal epithelial cell ferroptosis(Xu et al. 2020).
Our previous work showed that ferroptosis and the NF-κB signaling
pathway formed a positive feedback loop in hepatocyte inflammation
during the progression of NAFLD(Yao, Lan, Li, Wang and Qi 2023). We
hypothesize that ferroptosis in the kidney depends on the NF‑κB/NLRP3
pathway via P.g stimulation of M1 macrophage polarization during
the progression of CKD.
In the present study, a periodontitis model was constructed byP.g gavage, and the occurrence of periodontitis and CKD, M1
macrophage polarization, the NF‑κB pathway and ferroptosis in kidney
tissue were analyzed in vivo. Glomerular mesangial cells (GMCs)
stimulated with P.g were examined in vitro, and GMC
ferroptosis was activated through the NF‑κB/NLRP3 pathway by stimulating
M1 macrophage polarization with P.g supernatant.