BAFF is involved in the pathogenesis of IgA nephropathy by activating the TRAF6/NF‑κB signaling pathway in glomerular mesangial cells

Cao,Yingjie; Lu,Guoyuan; Chen,Xiaolan; Chen,Xu; Guo,Naifeng; Li,Wenwen

doi:10.3892/mmr.2019.10870

BAFF is involved in the pathogenesis of IgA nephropathy by activating the TRAF6/NF‑κB signaling pathway in glomerular mesangial cells

Authors:
- Yingjie Cao
- Guoyuan Lu
- Xiaolan Chen
- Xu Chen
- Naifeng Guo
- Wenwen Li
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Affiliations: Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, Department of Nephrology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
Published online on: December 6, 2019 https://doi.org/10.3892/mmr.2019.10870
Pages: 795-805
Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to investigate the involvement of B cell‑activating factor (BAFF) in the pathogenesis of IgA nephropathy by activating the tumor necrosis factor receptor‑associated factor 6 (TRAF6)/NF‑κB signaling pathway in glomerular mesangial cells. For the clinical analysis, blood, urine and kidney tissue samples were collected from 58 patients diagnosed with primary IgA nephropathy by renal biopsy. For the in vitro study, glomerular mesangial cells were divided into five groups: Control (con)‑short hairpin RNA (shRNA) (control group); con‑shRNA + BAFF (20 ng/ml); con‑shRNA + BAFF + BAFF‑RFc chimera protein (500 µg/ml); TRAF6‑shRNA; and TRAF6‑shRNA + BAFF (20 ng/ml). For the in vivo experiments, 60 Sprague‑Dawley rats were randomly divided into four groups: Con‑small interfering RNA (siRNA) (control group); con‑siRNA + IgA (IgA nephropathy group), BAFF‑RFc chimera protein (2 µg/ml) + IgA, and TRAF6‑siRNA (0.2 µM) + IgA. Reverse transcription‑quantitative PCR was performed to evaluate the mRNA expression levels of TRAF6, connective tissue growth factor (CTGF), fibronectin (FN) and NF‑κBP65. Western blot analysis was used to detect the protein expression levels of TRAF6, FN, CTGF and phosphorylated‑NF‑κBP65 in glomerular mesangial cells and kidney tissues. The results revealed that plasma BAFF levels were positively correlated with the severity of pathological damage in patients with IgA nephropathy. In vitro, BAFF induced the mRNA and protein expression of TRAF6, CTGF, FN and NF‑κBP65 in glomerular mesangial cells. After the BAFF‑RFc chimera protein was added to inhibit the binding of BAFF and BAFF‑receptor (‑R), this effect was reduced. In vivo, inhibition of the effects of BAFF via injection with the BAFF‑R Fc chimera protein reduced kidney damage in rats suffering from IgA nephropathy. The effect on the expression of signaling pathway‑associated proteins was also alleviated. In conclusion, BAFF enhanced the expression of fibroblast factors in the kidneys by activating the TRAF6/NF‑κB signaling pathway.

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1	Lee K, Shin J, Park J, Hwang S, Jang HR, Huh W, Kwon GY, Kim YG, Oh HY, Lee JE and Kim DJ: First-year GFR slope and long-term renal outcome in IgA nephropathy. Eur J Clin Invest. 48:e129362018. View Article : Google Scholar : PubMed/NCBI
2	Roberts IS: Pathology of IgA nephropathy. Nat Rev Nephrol. 10:445–454. 2014. View Article : Google Scholar : PubMed/NCBI
3	Coppo R: Treatment of IgA nephropathy: Recent advances and prospects. Nephrol Ther. 14 (Suppl 1):S13–S21. 2018. View Article : Google Scholar : PubMed/NCBI
4	Rauen T and Floege J: Inflammation in IgA nephropathy. Pediatr Nephrol. 32:2215–2224. 2017. View Article : Google Scholar : PubMed/NCBI
5	Coppo R: Biomarkers and targeted new therapies for IgA nephropathy. Pediatr Nephrol. 32:725–731. 2017. View Article : Google Scholar : PubMed/NCBI
6	Xie YX, He LY, Chen X, Peng XF, Ye MY, Zhao YJ, Yan WZ, Liu C, Shao J and Peng YM: Potential diagnostic biomarkers for IgA nephropathy: A comparative study pre- and post-tonsillectomy. Int Urol Nephrol. 48:1855–1861. 2016. View Article : Google Scholar : PubMed/NCBI
7	Li C, Shi J and Zhao Y: MiR-320 promotes B cell proliferation and the production of aberrant glycosylated IgA1 in IgA nephropathy. J Cell Biochem. 119:4607–4614. 2018. View Article : Google Scholar : PubMed/NCBI
8	Park SJ, Oh JY and Shin JI: Could increased IgA induced by BAFF be the cause of IgA nephropathy development in Behcet's disease? Comment on: Behcet's disease and IgA nephropathy (Rheumatol Int. 2012 Jul; 32(7):2227-9). Rheumatol Int. 34:283–284. 2014. View Article : Google Scholar : PubMed/NCBI
9	Zheng N, Wang D, Ming H, Zhang H and Yu X: BAFF promotes proliferation of human mesangial cells through interaction with BAFF-R. BMC Nephrol. 16:722015. View Article : Google Scholar : PubMed/NCBI
10	Ye M, Peng Y, Liu C, Yan W, Peng X, He L, Liu H and Liu F: Vibration induces BAFF overexpression and aberrant O-Glycosylation of IgA1 in cultured human tonsillar mononuclear cells in IgA nephropathy. Biomed Res Int. 2016:91259602016. View Article : Google Scholar : PubMed/NCBI
11	Zheng N, Fan J, Wang B, Wang D, Feng P, Yang Q and Yu X: Expression profile of BAFF in peripheral blood from patients of IgA nephropathy: Correlation with clinical features and Streptococcus pyogenes infection. Mol Med Rep. 15:1925–1935. 2017. View Article : Google Scholar : PubMed/NCBI
12	Shao J, Peng Y, He L, Liu H, Chen X and Peng X: Capsaicin induces high expression of BAFF and aberrantly glycosylated IgA1 of tonsillar mononuclear cells in IgA nephropathy patients. Hum Immunol. 75:1034–1039. 2014. View Article : Google Scholar : PubMed/NCBI
13	Xin G, Shi W, Xu LX, Su Y, Yan LJ and Li KS: Serum BAFF is elevated in patients with IgA nephropathy and associated with clinical and histopathological features. J Nephrol. 26:683–690. 2013. View Article : Google Scholar : PubMed/NCBI
14	McCarthy DD, Kujawa J, Wilson C, Papandile A, Poreci U, Porfilio EA, Ward L, Lawson MA, Macpherson AJ, McCoy KD, et al: Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy. J Clin Invest. 121:3991–4002. 2011. View Article : Google Scholar : PubMed/NCBI
15	Walsh MC, Lee J and Choi Y: Tumor necrosis factor receptor-associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol Rev. 266:72–92. 2015. View Article : Google Scholar : PubMed/NCBI
16	Kanaya T, Sakakibara S, Jinnohara T, Hachisuka M, Tachibana N, Hidano S, Kobayashi T, Kimura S, Iwanaga T, Nakagawa T, et al: Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-KB signaling. J Exp Med. 215:501–519. 2018. View Article : Google Scholar : PubMed/NCBI
17	Fang J, Muto T, Kleppe M, Bolanos LC, Hueneman KM, Walker CS, Sampson L, Wellendorf AM, Chetal K, Choi K, et al: TRAF6 mediates basal activation of NF-KB necessary for hematopoietic stem cell homeostasis. Cell Rep. 22:1250–1262. 2018. View Article : Google Scholar : PubMed/NCBI
18	Zhou Y, Jin XH, Jing YX, Song Y, He XX, Zheng LL, Wang YB, Wei ZY and Zhang GP: Porcine parvovirus infection activates inflammatory cytokine production through Toll-like receptor 9 and NF-KB signaling pathways in porcine kidney cells. Vet Microbiol. 207:56–62. 2017. View Article : Google Scholar : PubMed/NCBI
19	Cai M, Li M, Wang K, Wang S, Lu Q, Yan J, Mossman KL, Lin R and Zheng C: The herpes simplex virus 1-encoded envelope glycoprotein B activates NF-KB through the Toll-like receptor 2 and MyD88/TRAF6-dependent signaling pathway. PLoS One. 8:e545862013. View Article : Google Scholar : PubMed/NCBI
20	He X, Zheng Y, Liu S, Shi S, Liu Y, He Y, Zhang C and Zhou X: MiR-146a protects small intestine against ischemia/reperfusion injury by down-regulating TLR4/TRAF6/NF-KB pathway. J Cell Physiol. 233:2476–2488. 2018. View Article : Google Scholar : PubMed/NCBI
21	Wang P, Cao J, Liu S, Pan H, Liu X, Sui A, Wang L, Yao R, Liu Z and Liang J: Upregulated microRNA-429 inhibits the migration of HCC cells by targeting TRAF6 through the NF-KB pathway. Oncol Rep. 37:2883–2890. 2017. View Article : Google Scholar : PubMed/NCBI
22	Liu J, Zhang Z, Guo Q, Dong Y, Zhao Q and Ma X: Syringin prevents bone loss in ovariectomized mice via TRAF6 mediated inhibition of NF-KB and stimulation of PI3K/AKT. Phytomedicine. 42:43–50. 2018. View Article : Google Scholar : PubMed/NCBI
23	Zhong JH, Li J, Liu CF, Liu N, Bian RX, Zhao SM, Yan SY and Zhang YB: Effects of microRNA-146a on the proliferation and apoptosis of human osteoarthritis chondrocytes by targeting TRAF6 through the NF-KB signalling pathway. Biosci Rep. 37:BSR201605782017. View Article : Google Scholar : PubMed/NCBI
24	Guobing X, Lili J, Lihua Z and Tiean X: Application of an improved biuret method to the determination of total protein in urine and cerebrospinal fluid without concentration step by use of Hitachi 7170 auto-analyzer. J Clin Lab Anal. 15:161–164. 2001. View Article : Google Scholar : PubMed/NCBI
25	Shoker A, Hossain MA, Koru-Sengul T, Raju DL and Cockcroft D: Performance of creatinine clearance equations on the original Cockcroft-Gault population. Clin Nephrol. 66:89–97. 2006. View Article : Google Scholar : PubMed/NCBI
26	Katafuchi R, Kiyoshi Y, Oh Y, Uesugi N, Ikeda K, Yanase T and Fujimi S: Glomerular score as a prognosticator in IgA nephropathy: Its usefulness and limitation. Clin Nephrol. 49:1–8. 1998.PubMed/NCBI
27	Lei Y, Tang L, Xie Y, Xianyu Y, Zhang L, Wang P, Hamada Y, Jiang K, Zheng W and Jiang X: Gold nanoclusters-assisted delivery of NGF siRNA for effective treatment of pancreatic cancer. Nat Commun. 8:151302017. View Article : Google Scholar : PubMed/NCBI
28	Yang L, Wang Y, Nuerbiye A, Cheng P, Wang JH, Kasimu R and Li H: Effects of periostracum cicadae on cytokines and apoptosis regulatory proteins in an IgA nephropathy rat model. Int J Mol Sci. 19:E15992018. View Article : Google Scholar : PubMed/NCBI
29	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
30	He L, Peng X, Wang J, Tang C, Zhou X, Liu H, Liu F, Sun L and Peng Y: Synthetic Double-stranded RNA Poly(I:C) aggravates IgA nephropathy by triggering IgA class switching recombination through the TLR3-BAFF Axis. Am J Nephrol. 42:185–197. 2015. View Article : Google Scholar : PubMed/NCBI
31	Mackay F, Figgett WA, Saulep D, Lepage M and Hibbs ML: B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor. Immunol Rev. 237:205–225. 2010. View Article : Google Scholar : PubMed/NCBI
32	Li W, Peng X, Liu Y, Liu H, Liu F, He L, Liu Y, Zhang F, Guo C, Chen G, et al: TLR9 and BAFF: Their expression in patients with IgA nephropathy. Mol Med Rep. 10:1469–1474. 2014. View Article : Google Scholar : PubMed/NCBI
33	Tang X, Zhang L and Wei W: Roles of TRAFs in NF-KB signaling pathways mediated by BAFF. Immunol Lett. 196:113–118. 2018. View Article : Google Scholar : PubMed/NCBI
34	Tian J, Jiao X, Wang X, Geng J, Wang R, Liu N, Gao X, Griffin N and Shan F: Novel effect of methionine enkephalin against influenza A virus infection through inhibiting TLR7-MyD88-TRAF6-NF-KB p65 signaling pathway. Int Immunopharmacol. 55:38–48. 2018. View Article : Google Scholar : PubMed/NCBI
35	Hildebrand JM, Luo Z, Manske MK, Price-Troska T, Ziesmer SC, Lin W, Hostager BS, Slager SL, Witzig TE, Ansell SM, et al: A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling. J Exp Med. 207:2569–2579. 2010. View Article : Google Scholar : PubMed/NCBI
36	Chen JX, Shen HH, Niu M, Guo YM, Liu XQ, Han YZ, Zhang YM, Zhao YL, Bai BK, Zhou WJ and Xiao XH: Anti-hepatitis B virus effect of matrine-type alkaloid and involvement of p38 mitogen-activated protein kinase and tumor necrosis factor receptor-associated factor 6. Virus Res. 215:104–113. 2016. View Article : Google Scholar : PubMed/NCBI
37	Xu LG and Shu HB: TNFR-associated factor-3 is associated with BAFF-R and negatively regulates BAFF-R-mediated NF-kappa B activation and IL-10 production. J Immunol. 169:6883–6889. 2002. View Article : Google Scholar : PubMed/NCBI
38	Pullen SS, Dang TT, Crute JJ and Kehry MR: CD40 signaling through tumor necrosis factor receptor-associated factors (TRAFs). Binding site specificity and activation of downstream pathways by distinct TRAFs. J Biol Chem. 274:14246–14254. 1999. View Article : Google Scholar : PubMed/NCBI