Objective To investigate the relationship between free mitochondrial DNA (mtDNA) level in outflow dialysate and chronic peritoneum inflammation in patients undergoing peritoneal dialysis (PD). Methods A total of 85 patients with PD for more than 6 months were enrolled and divided into group A (using dialysate with 1.5% glucose) and group B (using dialysate with 2.5% or 4.25% glucose more than twice a day). Blood samples were collected and serum biochemical parameters were tested. The outflow dialysate was collected to measure interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-18 (IL-18) and free mtDNA in the fluid. The differences of these parameters were compared between the two groups. The correlation between mtDNA in outflow dialysate and clinical parameters was analyzed. Multivariate regression was used to define the risk factors for mtDNA in dialysate. Results PD duration was longer (t=-2.206, P=0.030) and serum albumin was lower (t=2.635, P=0.010) in group B than in group A. IL-6, TNF-α, IL-1β, IL-18 and free mtDNA in the dialysate were significantly higher in group B than in group A (t=-4.835, -6.557, -2.395, -2.318 and -3.920 respectively; P<0.001, <0.001, =0.019, =0.023 and <0.001 respectively). Free mtDNA level in the dialysate was positively correlated with the levels of IL-6, TNF-α, IL-1β and IL-18 in dialysate and PD duration (r=0.721, 0.418, 0.771, 0.634 and 0.240 respectively; P<0.001, <0.001, <0.001 and =0.03 respectively), and was negatively correlated with serum Alb (r=-0.319, P<0.01). Multivariate linear regression showed that higher glucose concentration in dialysate (β=0.358, P=0.005), longer PD duration (β=0.292, P=0.000) and lower serum Alb concentration (β=-0.272, P=0.027) were the risk factors for higher free mtDNA in outflow dialysate. Conclusion Elevated mtDNA in outflow dialysate is associated with chronic micro-inflammatory status of the peritoneum in PD patients. Higher glucose concentration in dialysate, longer PD duration and lower serum Alb concentration are the risk factors for higher free mtDNA in outflow dialysate.
[1]Hamada C,Tomino Y.Recent Understanding of Peritoneal Pathology in Peritoneal Dialysis Patients in Japan[J].Blood Purif,2021,50(6):719-728.
[2]Helmke A,Hüsing AM,Gaedcke S,et al.Peritoneal dialysate-range hypertonic glucose promotes T-cell IL-17 production that induces mesothelial inflammation[J]. Eur J Immunol,2021,51(2):354-367.
[3]Vareesangthip K,Vongsanim S,Fan S,et al.Comparison between standard single chamber versus dual chamber low glucose degradation product peritoneal dialysis fluids[J].Artif Organs,2021,45(1):88-94.
[4]Li S,Li H,Zhang YL,et al.SFTSV Infection Induces BAK/BAX-Dependent Mitochondrial DNA Release to Trigger NLRP3 Inflammasome Activation[J].Cell Rep,2020,30(13):4370-4385.
[5]Fei Q,Ma H,Zou J,et al.Metformin protects against ischaemic myocardial injury by alleviating autophagy-ROS-NLRP3-mediated inflammatory response in macrophages[J].J Mol Cell Cardiol,2020,145(4):1-13.
[6]Chen YT,Hsu H,Lin CC,et al.Inflammatory macrophages switch to CCL17-expressing phenotype and promote peritoneal fibrosis[J].J Pathol,2020, 250(1):55-66.
[7]Xie X,Wang J,Xiang S,et al.Dialysate cell-free mitochondrial DNA fragments as a marker of intraperitoneal inflammation and peritoneal solute transport rate in peritoneal dialysis[J].BMC Nephrol,2019,20(1):128-135.
[8]Pereira CV,Gitschlag BL,Patel MR.Cellular mechanisms of mtDNA heteroplasmy dynamics[J].Crit Rev Biochem Mol Biol,2021,56(5):510-525.
[9]Yan C,Duanmu X,Zeng L,et al.Mitochondrial DNA:Distribution,Mutations,and Elimination[J].Cells,2019,,8(4):379-394.
[10]Castellani CA,Longchamps RJ,Sun J,et al.Thinking outside the nucleus:Mitochondrial DNA copy number in health and disease[J].Mitochondrion, 2020,53(3):214-223.
[11]Nie S,Lu J,Wang L,et al.Pro-inflammatory role of cell-free mitochondrial DNA in cardiovascular diseases[J].IUBMB Life,2020,72(9):1879-1890.
[12]Ohlsson L,Hall A,Lindahl H,et al.Increased level of circulating cell-free mitochondrial DNA due to a single bout of strenuous physical exercise[J].Eur J Appl Physiol,2020,120(4):897-905.
[13]Kowalczyk P,Sulejczak D,Kleczkowska P,et al.Mitochondrial oxidative Stress-A causative factor and therapeutic target in many diseases[J].Int J Mol Sci,2021,22(24):13384-13402.
[14]Tian L,Yu Q,Liu D,et al.Epithelial-mesenchymal Transition of Peritoneal Mesothelial Cells Is Enhanced by M2c Macrophage Polarization[J].Immunol Invest,2022,51(2):301-315.
[15]Li X,Liu H,Sun L,et al.MicroRNA-302c modulates peritoneal dialysis-associated fibrosis by targeting connective tissue growth factor[J].J Cell Mol Med,2019, 23(4):2372-2383.
[16]Parveen A,Sultana R,Lee SM,et al.Phytochemicals against anti-diabetic complications:targeting the advanced glycation end product signaling pathway[J].Arch Pharm Res,2021,44(4):378-401.
[17]Fonseca LF,Araújo AB,Quadros KRDS,et al.AGEs accumulation is related to muscle degeneration and vascular calcification in peritoneal dialysis patients[J].J Bras Nefrol,2021,43(2):191-199.
[18]Lin CP,Huang PH,Chen CY,et al.Sitagliptin attenuates arterial calcification by downregulating oxidative stress-induced receptor for advanced glycation end products in LDLR knockout mice[J].Sci Rep,2021,11(1):17851-17865.
[19]Zhang P,Dai H,Peng L.AGEs induce epithelial to mesenchymal transformation of human peritoneal mesothelial cells via upregulation of STAT3[J].Glycoconj J,2019,36(2):155-163.
[20]Jing R,Hu ZK,Lin F,et al.Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB Pathway[J].Front Cell Dev Biol,2020,8(5):819-834.
[21]Li Z,Feng J,Yang S,et al.Lipopolysaccharide-induced inflammation in human peritoneal mesothelial cells is controlled by ERK1/2-CDK5-PPARγ axis[J].Ann Transl Med,2021,9(10):850-861.
[22]Yang X,Yan H,Jiang N,et al.IL-6 trans-signaling drives a STAT3-dependent pathway that leads to structural alterations of the peritoneal membrane[J].Am J Physiol Renal Physiol[J].2020,318(2):F338-F353.
[23]Catar R,Witowski J,Zhu N,et al.IL-6 Trans-Signaling Links Inflammation with Angiogenesis in the Peritoneal Membrane[J].J Am Soc Nephrol,2017,28(4):1188-1199.
[24]Jiang N,Zhang Q,Chau MK,et al.Anti-fibrotic effect of decorin in peritoneal dialysis and PD-associated peritonitis[J].EBioMedicine,2020,52(4):102661.
[25]Zhang W,Li G,Luo R,et al.Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis[J].Exp Mol Med,2022,54(2):129-142.
[26]Ko J,Kang HJ,Kim DA,et al.Paricalcitol attenuates TGF-β1-induced phenotype transition of human peritoneal mesothelial cells (HPMCs) via modulation of oxidative stress and NLRP3 inflammasome[J].FASEB J,2019,33(2):3035-3050.
[27]Zhao M,Wang Y,Li L,et al.Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance[J].Theranostics,2021,11(4):1845-1863.
[28]Guo Y,Gu R,Gan D,et al.Mitochondrial DNA drives noncanonical inflammation activation via cGAS-STING signaling pathway in retinal microvascular endothelial cells[J].Cell Commun Signal,2020,18(1):172-184.
[29]Bai D,Du J,Bu X,et al.ALDOA maintains NLRP3 inflammasome activation by controlling AMPK activation[J].Autophagy,2022,18(7):1673-1693.