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In situ glomerular expression of activated NF-κB in human lupus nephritis and other non-proliferative proteinuric glomerulopathy

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Abstract

Nuclear Factor-κB (NF-κB) has been suggested to play a role in the cellular and molecular mechanisms underlying glomerular injury. We investigated the potential role of NF-κB activation in the pathogenesis of glomerular injury in 31 patients with class III–V lupus nephritis (LN), 14 patients with non-proliferative proteinuric glomerulopathy and six normal controls. The expression of NF-κB subunits p65 and p50, and the NF-κB regulated proinflammatory mediators tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) as well as CD68 and synaptopodin was examined by Southwestern histochemistry (SWH) or immunohistochemistry. In contrast to non-proliferative glomerulopathy and normal controls, NF-κB activation (both p65 and p50) was enhanced in glomerular endothelial, mesangial cells or infiltrating cells in class IV LN, along with upregulation of TNF-α, IL-1β, IL-6 and ICAM-1 expression. Glomerular endothelial and mesangial activation of NF-κB and mesangial ICAM-1 expression correlated with disease activity and the level of glomerular macrophage infiltration. Podocyte NF-κB overactivation (predominantly p65) paralleled podocyte expression of TNF-α and IL-1β in patients with LN and non-proliferative glomerulopathy. Podocyte staining scores of NF-κB and p65 were positively correlated with the severity of proteinuria in LN and non-proliferative glomerulopathy. These results suggest a pathogenic role for NF-κB in glomerular injury by multiple mechanisms.

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Abbreviations

IMN:

idiopathic membranous nephropathy

ICAM-1:

intercellular adhesion molecule-1

IL-1β:

interleukin-1β

IL-6:

interleukin-6

LN:

lupus nephritis

MCD:

minimal change disease

NF-κB:

nuclear factor-kappaB

SWH:

southwestern histochemistry

TNF-α:

tumor necrosis factor-α

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Acknowledgements

We wish to acknowledge the support from National University of Singapore. This work was undertaken in the Special Histopathology laboratory in the Department of Pathology. We thank Dr. Koh Dow Rhoon for valuable advice and Dr. Thian Chai Lee (Johor Specialist Center, Malaysia) for his assistance in providing the clinical data on the biopsy cases included in the present study. This work was funded by Academic Research Fund Grant R-172-000-109-112 to R.S. and S.I.-H.H., and intramural funding from the Department of Medicine, National University of Singapore.

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Author notes

  1. Raja Sinniah

    Present address: Department of Anatomical Pathology, Royal Perth Hospital, University of Western Australia, Wellington Street Campus, P.O. Box X22123 GPO, Perth, 6847, Australia

  2. Stephen I-Hong Hsu

    Present address: Renal Division and Department of Medicine, Brigham and Women's Hospital, Harvard Institutes of Medicine, Rm. 554, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA

Authors and Affiliations

  1. Department of Pathology, National University of Singapore, Singapore, Singapore

    Ling Zheng

  2. Department of Medicine, National University Hospital, 5 Lower Kent Ridge Road, 119074, Singapore, Singapore

    Stephen I-Hong Hsu

  3. Genome Institute of Singapore, 60 Biopolis St., Genome #02-014, 138672, Genome, Singapore

    Stephen I-Hong Hsu

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  1. Ling Zheng
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Correspondence to Stephen I-Hong Hsu.

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Zheng, L., Sinniah, R. & I-Hong Hsu, S. In situ glomerular expression of activated NF-κB in human lupus nephritis and other non-proliferative proteinuric glomerulopathy. Virchows Arch 448, 172–183 (2006). https://doi.org/10.1007/s00428-005-0061-9

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