Top

BMC Nephrology

Published in:

Open Access 01-12-2015 | Research article

Methylprednisolone attenuates lipopolysaccharide-induced Fractalkine expression in kidney of Lupus-prone MRL/lpr mice through the NF-kappaB pathway

Authors: Yanwu You, Yueqiu Qin, Xu Lin, Fafen Yang, Jun Li, Suren R. Sooranna, Liao Pinhu

Published in: BMC Nephrology | Issue 1/2015

Abstract

Background

Fractalkine (FKN) is involved in the occurrence and development of human lupus nephritis. It is known to be upregulated by lipopolysaccharide (LPS) as a stimulus in vivo. MRL/lpr mice have been used as an in vivo model to study lupus nephritis. Methylprednisolone (MP) is used widely in the clinical treatment of progressive glomerular diseases such as lupus nephritis. The aim of this study is to explore the mechanism of LPS induced FKN expression and to determine whether other molecular mechanisms contribute to the signaling pathway of MP action in MRL/lpr mice.

Methods

Forty-eight female MRL/lpr mice at 12 weeks of age were randomly distributed into six groups. Each group received various treatments for 8 weeks by receiving twice weekly intraperitoneal injections of (1) MP (MP-treated mice), of (2) SC-514 (SC-514-induced mice), of (3) normal saline and a single injection of LPS (LPS-induced mice), of (4) MP and a single injection of LPS (LPS + MP mice), of (5) SC-514 and a single injection of LPS (LPS + SC mice) and of (6) normal saline (control mice). One-way ANOVA was used for data analysis and P value <0.05 was considered statistically significantly.

Results

The expression of FKN and NF-kappaB p65 mRNA was detected by qPCR. The expression of FKN protein and the activation of NF-kappaB p65 were detected by immunohistochemistry and western blots respectively. The expression of FKN in the kidney of LPS induced mice was significantly increased and this was mediated by increased expression of NF-κB p65 and an increase in NF-kappaB phospho-p65. MP reduced proteinuria and ameliorated the renal damage in MRL/lpr mice. MP as well as the NF-kappaB inhibitor, SC-514, inhibited the LPS-induced increase of expression of FKN and the activation of NF-kappaB.

Conclusions

The results indicate that MP attenuates LPS-induced FKN expression in kidney of MRL/lpr mice through the NF-kappaB pathway.

Cameron JS. Lupus nephritis. J Am Soc Nephrol. 1999;10(2):413–24.PubMed

Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65(2):521–30.PubMed

Iwata Y, Furuichi K, Kaneko S, Wada T. The role of cytokine in the lupus nephritis. J Biomed Biotechnol. 2011;2011:594809.PubMedPubMedCentral

Koziolek MJ, Vasko R, Bramlage C, Muller GA, Strutz F. The CX(3)C-chemokine fractalkine in kidney diseases. Mini Rev Med Chem. 2009;9(10):1215–28.PubMed

Hoffmann U, Bergler T, Segerer S, Rummele P, Kruger B, Banas MC, et al. Impact of chemokine receptor CX3CR1 in human renal allograft rejection. Transpl Immunol. 2010;23(4):204–8.PubMed

Koziolek MJ, Muller GA, Zapf A, Patschan D, Schmid H, Cohen CD, et al. Role of CX3C-chemokine CX3C-L/fractalkine expression in a model of slowly progressive renal failure. Nephrol Dial Transplant. 2010;25(3):684–98.PubMed

Shimizu K, Furuichi K, Sakai N, Kitagawa K, Matsushima K, Mukaida N, et al. Fractalkine and its receptor, CX3CR1, promote hypertensive interstitial fibrosis in the kidney. Hypertens Res. 2011;34(6):747–52.PubMed

Yoshimoto S, Nakatani K, Iwano M, Asai O, Samejima K, Sakan H, et al. Elevated levels of fractalkine expression and accumulation of CD16+ monocytes in glomeruli of active lupus nephritis. Am J Kidney Dis. 2007;50(1):47–58.PubMed

Chen YM, Hu-Tsai MI, Lin SL, Tsai TJ, Hsieh BS. Expression of CX3CL1/fractalkine by mesangial cells in vitro and in acute anti-Thy1 glomerulonephritis in rats. Nephrol Dial Transplant. 2003;18(12):2505–14.PubMed

10.

Katsuyama K, Fujinaka H, Yamamoto K, Nameta M, Yaoita E, Yoshida Y, et al. Expression of the chemokine fractalkine (FKN/CX3CL1) by podocytes in normal and proteinuric rat kidney glomerulus. Nephron Exp Nephrol. 2009;113(2):e45–56.PubMed

11.

Zhai JX, Zhang ZX, Feng YJ, Ding SS, Wang XH, Zou LW, et al. PDTC attenuate LPS-induced kidney injury in systemic lupus erythematosus-prone MRL/lpr mice. Mol Biol Rep. 2012;39(6):6763–71.PubMed

12.

Nakatani K, Yoshimoto S, Iwano M, Asai O, Samejima K, Sakan H, et al. Fractalkine expression and CD16+ monocyte accumulation in glomerular lesions: association with their severity and diversity in lupus models. Am J Physiol Renal Physiol. 2010;299(1):F207–216.PubMed

13.

Durkan AM, Alexander RT, Liu GY, Rui M, Femia G, Robinson LA. Expression and targeting of CX3CL1 (fractalkine) in renal tubular epithelial cells. J Am Soc Nephrol. 2007;18:74–83.PubMed

14.

Inoue A, Hasegawa H, Kohno M, Ito MR, Terada M, Imai T, et al. Antagonist of fractalkine (CX3CL1) delays the initiation and ameliorates the progression of lupus nephritis in MRL/lpr mice. Arthritis Rheum. 2005;52(5):1522–33.PubMed

15.

Kalergis AM, Iruretagoyena MI, Barrientos MJ, Gonzalez PA, Herrada AA, Leiva ED, et al. Modulation of nuclear factor-kappaB activity can influence the susceptibility to systemic lupus erythematosus. Immunology. 2009;128(1 Suppl):e306–314.PubMedPubMedCentral

16.

Pawar RD, Castrezana-Lopez L, Allam R, Kulkarni OP, Segerer S, Radomska E, et al. Bacterial lipopeptide triggers massive albuminuria in murine lupus nephritis by activating Toll-like receptor 2 at the glomerular filtration barrier. Immunology. 2009;128(1 Suppl):e206–221.PubMedPubMedCentral

17.

Wu F, Zhang W, Li L, Zheng F, Shao X, Zhou J, et al. Inhibitory effects of honokiol on lipopolysaccharide-induced cellular responses and signaling events in human renal mesangial cells. Eur J Pharmacol. 2011;654(1):117–21.PubMed

18.

Park J, Song KH, Ha H. Lipopolysaccharide increases monocyte binding to mesangial cells through fractalkine and its receptor. Transplant Proc. 2012;44(4):1029–31.PubMed

19.

Park J, Song KH, Ha H. Fractalkine increases mesangial cell proliferation through reactive oxygen species and mitogen-activated protein kinases. Transplant Proc. 2012;44(4):1026–8.PubMed

20.

Wilhelmus S, Bajema IM, Bertsias GK, Boumpas DT, Gordon C, Lightstone L, Tesar V, Jayne DR. Lupus nephritis management guidelines compared. Nephrol Dial Transplant. 2015. [Epub ahead of print].

21.

Benseler SM, Bargman JM, Feldman BM, Tyrrell PN, Harvey E, Hebert D, et al. Acute renal failure in paediatric systemic lupus erythematosus: treatment and outcome. Rheumatology (Oxford). 2009;48(2):176–82.

22.

Molino C, Fabbian F, Longhini C. Clinical approach to lupus nephritis: recent advances. Eur J Intern Med. 2009;20(5):447–53.PubMed

23.

Bhavsar PK, Sukkar MB, Khorasani N, Lee KY, Chung KF. Glucocorticoid suppression of CX3CL1 (fractalkine) by reduced gene promoter recruitment of NF-kappaB. FASEB J. 2008;22(6):1807–16.PubMed

24.

Jamart C, Gomes AV, Dewey S, Deldicque L, Raymackers JM, Francaux M. Regulation of ubiquitin-proteasome and autophagy pathways after acute LPS and epoxomicin administration in mice. BMC Musculoskelet Disord. 2014;15:166.PubMedPubMedCentral

25.

Ka SM, Rifai A, Chen JH, Cheng CW, Shui HA, Lee HS, et al. Glomerular crescent-related biomarkers in a murine model of chronic graft versus host disease. Nephrol Dial Transplant. 2006;21(2):288–98.PubMed

26.

Pinhu L, Park JE, Yao W, Griffiths MJ. Reference gene selection for real-time polymerase chain reaction in human lung cells subjected to cyclic mechanical strain. Respirology. 2008;13(7):990–9.PubMed

27.

Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101–8.PubMed

28.

Muller HK, Wegener G, Popoli M, Elfving B. Differential expression of synaptic proteins after chronic restraint stress in rat prefrontal cortex and hippocampus. Brain Res. 2011;1385:26–37.PubMed

29.

Susianti H, Iriane VM, Dharmanata S, Handono K, Widijanti A, Gunawan A, et al. Analysis of urinary TGF-beta1, MCP-1, NGAL, and IL-17 as biomarkers for lupus nephritis. Pathophysiology. 2015;22(1):65–71.PubMed

30.

Abujam B, Cheekatla S, Aggarwal A. Urinary CXCL-10/IP-10 and MCP-1 as markers to assess activity of lupus nephritis. Lupus. 2013;22(6):614–23.PubMed

31.

Bauer JW, Petri M, Batliwalla FM, Koeuth T, Wilson J, Slattery C, et al. Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. Arthritis Rheum. 2009;60(10):3098–107.PubMedPubMedCentral

32.

Dominguez-Gutierrez PR, Ceribelli A, Satoh M, Sobel ES, Reeves WH, Chan EK. Elevated signal transducers and activators of transcription 1 correlates with increased C-C motif chemokine ligand 2 and C-X-C motif chemokine 10 levels in peripheral blood of patients with systemic lupus erythematosus. Arthritis Res Ther. 2014;16(1):R20.PubMedPubMedCentral

33.

Dominguez-Gutierrez PR, Ceribelli A, Satoh M, Sobel ES, Reeves WH, Chan EK. Reduced levels of CCL2 and CXCL10 in systemic lupus erythematosus patients under treatment with prednisone, mycophenolate mofetil, or hydroxychloroquine, except in a high STAT1 subset. Arthritis Res Ther. 2014;16(1):R23.PubMedPubMedCentral

34.

Kulkarni O, Pawar RD, Purschke W, Eulberg D, Selve N, Buchner K, et al. Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice. J Am Soc Nephrol. 2007;18(8):2350–8.PubMed

35.

Kassianos AJ, Wang X, Sampangi S, Afrin S, Wilkinson R, Healy H. Fractalkine-CX3CR1-dependent recruitment and retention of human CD1c(+) myeloid dendritic cells by in vitro-activated proximal tubular epithelial cells. Kidney Int. 2015;87(6):1153–63.PubMed

36.

Khan IU, Tsokos GC, Kammer GM. Abnormal B cell signal transduction in systemic lupus erythematosus. Curr Dir Autoimmun. 2003;6:89–104.PubMed

37.

Badr G, Sayed A, Abdel-Maksoud MA, Mohamed AO, El-Amir A, Abdel-Ghaffar FA, et al. Infection of Female BWF1 Lupus Mice with Malaria Parasite Attenuates B Cell Autoreactivity by Modulating the CXCL12/CXCR4 Axis and Its Downstream Signals PI3K/AKT, NFkappaB and ERK. PLoS One. 2015;10(4), e0125340.PubMedPubMedCentral

38.

Guo X, Pan Y, Xiao C, Wu Y, Cai D, Gu J. Fractalkine stimulates cell growth and increases its expression via NF-kappaB pathway in RA-FLS. Int J Rheum Dis. 2012;15(3):322–9.PubMed

Title: Methylprednisolone attenuates lipopolysaccharide-induced Fractalkine expression in kidney of Lupus-prone MRL/lpr mice through the NF-kappaB pathway
Authors: Yanwu You
Yueqiu Qin
Xu Lin
Fafen Yang
Jun Li
Suren R. Sooranna
Liao Pinhu
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Nephrology / Issue 1/2015
Electronic ISSN: 1471-2369
DOI: https://doi.org/10.1186/s12882-015-0145-y

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Methylprednisolone attenuates lipopolysaccharide-induced Fractalkine expression in kidney of Lupus-prone MRL/lpr mice through the NF-kappaB pathway

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

End stage renal disease as a modifier of the periodontal microbiome

Factors affecting willingness to receive a kidney transplant among minority patients at an urban safety-net hospital: a cross-sectional survey

Routine serum creatinine measurements: how well do we perform?

Focal segmental glomerulosclerosis: molecular genetics and targeted therapies

Strategy and rationale for urine collection protocols employed in the NEPTUNE study

Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page