TLR2-MyD88-NF-κB pathway is involved in tubulointerstitial inflammation caused by proteinuria.
Proteinuria is an important risk factor for chronic kidney diseases (CKD). Several studies have suggested that proteinuria initiates tubulointerstitial inflammation, while the mechanisms have not been fully understood. In this study, we hypothesized whether the activation of the TLR2-MyD88-NF-κB pathway is involved in tubulointerstitial inflammation induced by proteinuria. We observed expression of TLR2, MyD88, NF-κB, as well as TNF-α and IL-6 detected by immunohistostaining, Western blotting and real-time PCR in albumin-overloaded (AO) nephropathy rats. In vitro, we observed these markers in HK-2 cells stimulated by albumin. We used TLR2 siRNA or the NF-κB inhibitor BAY 11-7082 to observe the influence of TNF-α and IL-6 expression caused by albumin overload. Finally, we studied these markers in non-IgA mesangioproliferative glomerulonephritis (MsPGN) patients with different levels of proteinuria. It was demonstrated that expression of TLR2, MyD88 and NF-κB were significantly increased in AO rats and in non-IgA MsPGN patients with high levels of proteinuria, and TNF-α and IL-6 expressions were increased after NF-κB activation. Furthermore, TNF-α and IL-6 expression was positively correlated with the level of proteinuria. Albumin-overload induced TNF-α and IL-6 secretions by the TLR2-MyD88-NF-κB pathway activation, which could be attenuated by the TLR2 siRNA or BAY 11-7082 in HK-2 cells. In summary, we demonstrated that proteinuria may exhibit an endogenous danger-associated molecular pattern (DAMP) that induces tubulointerstitial inflammation via the TLR2-MyD88-NF-κB pathway activation.
Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
Li-Hong
LH
Ding
Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
Dan
D
Liu
Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
Min
M
Xu
Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
Min
M
Wu
Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
Hong
H
Liu
Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
Ri-Ning
RN
Tang
Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
Kun-Ling
KL
Ma
Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
Ping-Sheng
PS
Chen
Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China. Electronic address: liubc64@163.com.
Bi-Cheng
BC
Liu
D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D011507:Proteinuria / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D017208:Rats, Wistar; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D015850:Interleukin-6; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C495343:Tlr2 protein, rat; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha
IL-6; Proteinuria; TLR2–MyD88–NF-κB pathway; TNF-α; Tubulointerstitial inflammation