Crosstalk between TLR4 and Notch1 signaling in the IgA nephropathy during inflammatory response
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Abstract
Purpose
IgA nephropathy (IgAN) is an immune complex-mediated disease involved in the kidney disease. Recent studies have revealed that Notch signaling-related genes are aberrantly expressed in various cell types and maybe associate with inflammation-induced carcinogenesis. The aim of our study was to investigate the function of Notch1 in the inflammatory response of IgAN.
Methods
The expression of Notch1, Jagged1 and NICD1 in 52 IgAN renal tissues and 20 control renal tissues was first determined using quantitative real-time PCR and Western blot. ELISA was then used to estimate the inflammatory response of human podocytes to LPS. NF-κB activity was measured using dual-luciferase reporter assay. Activation of Notch1 and NF-κB signaling pathway was assessed using Western blot.
Results
The expression of Notch1, NICD1 and Jagged1 was significantly higher in IgAN renal tissues than control renal tissues (P < 0.05). LPS treatment resulted in an obvious increase of MCP-1, IL-8 and phosphorylated NF-κB p65 in podocytes polymeric IgA (pIgA) IgAN group compared to control group (P < 0.05 for all). Activated Notch1 and its target genes, Hes1 and Hey1 were also enhanced upon LPS stimulation. Silencing of Notch1 signaling with inhibitor DAPT, NF-κB activation and LPS-induced inflammatory response were obviously attenuated, whereas Notch1 activator Jagged1 could markedly restore NF-κB activity and LPS-induced inflammatory response (P < 0.05 for all).
Conclusions
Crosstalk between TLR4 and Notch1 signaling regulates the inflammatory response in the IgAN and maybe plays an important role in the progression of IgAN.
Keywords
IgA nephropathy Notch1 Toll-like receptor 4 Innate immunityNotes
Acknowledgements
We thank all the staff in the department of Nephrology of Linyi People’s Hospital for their help on the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
References
- 1.Wyatt RJ, Julian BA (2013) IgA nephropathy. N Engl J Med 368:2402–2414CrossRefPubMedGoogle Scholar
- 2.Coppo R, Amore A, Peruzzi L, Vergano L, Camilla R (2010) Innate immunity and IgA nephropathy. J Nephrol 23:626–632PubMedGoogle Scholar
- 3.Kaisho T, Akira S (2006) Toll-like receptor function and signaling. J Allergy Clin Immunol 117:979–987CrossRefPubMedGoogle Scholar
- 4.Medzhitov R, Janeway C Jr (2000) Innate immune recognition: mechanisms and pathways. Immunol Rev 173:89–97CrossRefPubMedGoogle Scholar
- 5.Means TK, Golenbock DT, Fenton MJ (2000) The biology of Toll-like receptors. Cytokine Growth Factor Rev 11:219–232CrossRefPubMedGoogle Scholar
- 6.Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K et al (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189:1777–1782CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR et al (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099–1103CrossRefPubMedGoogle Scholar
- 8.Coppo R, Camilla R, Amore A, Peruzzi L, Daprà V, Loiacono E et al (2010) Toll-like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy. Clin Exp Immunol 159:73–81CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Suzuki H, Suzuki Y, Narita I, Aizawa M, Kihara M, Yamanaka T et al (2008) Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol 19:2384–2395CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Machida H, Ito S, Hirose T, Takeshita F, Oshiro H, Nakamura T et al (2010) Expression of Toll-like receptor 9 in renal podocytes in childhood-onset active and inactive lupus nephritis. Nephrol Dial Transpl 25:2530–2537CrossRefGoogle Scholar
- 11.Saurus P, Kuusela S, Lehtonen E, Hyvönen ME, Ristola M, Fogarty CL et al (2015) Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway. Cell Death Dis 6:e1752CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Ilagan MX, SnapShot KR (2007) Notch signaling pathway. Cell 128:1246CrossRefPubMedGoogle Scholar
- 13.Kopan R, Cagan R (1997) Notch on the cutting edge. Trends Genet 13:465–467CrossRefPubMedGoogle Scholar
- 14.Bajaj J, Maliekal TT, Vivien E, Pattabiraman C, Srivastava S, Krishnamurthy H et al (2011) Notch signaling in CD66 + cells drives the progression of human cervical cancers. Cancer Res 71:4888–4897CrossRefPubMedGoogle Scholar
- 15.Li L, Tan J, Zhang Y, Han N, Di X, Xiao T et al (2014) DLK1 promotes lung cancer cell invasion through upregulation of MMP9 expression depending on Notch signaling. PLoS ONE 9:e91509CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Stylianou S, Clarke RB, Brennan K (2006) Aberrant activation of notch signaling in human breast cancer. Cancer Res 66:1517–1525CrossRefPubMedGoogle Scholar
- 17.Lai KN, Leung JC, Chan LY, Saleem MA, Mathieson PW, Lai FM et al (2005) Activation of tubular epithelial cells by mesangial-derived TNF-α: glomerulo-tubular communication in IgA nephropathy. Kidney Int 67:602–612CrossRefPubMedGoogle Scholar
- 18.Lai KN (2012) Pathogenesis of IgA nephropathy. Nat Rev Nephrol 8:275–283CrossRefPubMedGoogle Scholar
- 19.Roberts IS (2014) Pathology of IgA nephropathy. Nat Rev Nephrol 10:445–454CrossRefPubMedGoogle Scholar
- 20.Robert T, Berthelot L, Cambier A, Rondeau E, Monteiro RC (2015) Molecular insights into the pathogenesis of IgA nephropathy. Trends Mol Med 21:762–775CrossRefPubMedGoogle Scholar
- 21.Duque N, Gómez-Guerrero C, Egido J (1997) Interaction of IgA with Fc alpha receptors of human mesangial cells activates transcription factor nuclear factor-kappa B and induces expression and synthesis of monocyte chemoattractant protein-1, IL-8, and IFN-inducible protein 10. J Immunol 159:3474–3482PubMedGoogle Scholar
- 22.Waters AM, Wu MY, Onay T, Scutaru J, Liu J, Lobe CG et al (2008) Ectopic notch activation in developing podocytes causes glomerulosclerosis. J Am Soc Nephrol 19:1139–1157CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Murea M, Park JK, Sharma S, Kato H, Gruenwald A, Niranjan T et al (2010) Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function. Kidney Int 78:514–522CrossRefPubMedGoogle Scholar
- 24.Kavanagh D, McKay GJ, Patterson CC, McKnight AJ, Maxwell AP, Savage DA (2011) Warren 3/UK GoKinD Study Group. association analysis of Notch pathway signalling genes in diabetic nephropathy. Diabetologia 54:334–338CrossRefPubMedGoogle Scholar
- 25.Sweetwyne MT, Gruenwald A, Niranjan T, Nishinakamura R, Strobl LJ, Susztak K (2015) Notch1 and Notch2 in podocytes play differential roles during diabetic nephropathy development. Diabetes 64:4099–4111CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Ueno T, Kobayashi N, Nakayama M, Takashima Y, Ohse T, Pastan I et al (2013) Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss. Kidney Int 83:1065–1075CrossRefPubMedGoogle Scholar
- 27.Zeng Q, Jin C, Ao L, Cleveland JC Jr, Song R, Xu D et al (2012) Cross-talk between the Toll-like receptor 4 and Notch1 pathways augments the inflammatory response in the interstitial cells of stenotic human aortic valves. Circulation 126:222–230CrossRefGoogle Scholar
- 28.Zeng Q, Song R, Ao L, Weyant MJ, Lee J, Xu D et al (2013) Notch1 promotes the pro-osteogenic response of human aortic valve interstitial cells via modulation of ERK1/2 and nuclear factor-κB activation. Arterioscler Thromb Vasc Biol 33:1580–1590CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Li L, Zhang J, Xiong N, Li S, Chen Y, Yang H et al (2016) Notch-1 signaling activates NF-κB in human breast carcinoma MDA-MB-231 cells via PP2A-dependent AKT pathway. Med Oncol 33:33CrossRefPubMedGoogle Scholar