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

Abstract

Nuclear Factor-kappaB (NF-kappaB) has been suggested to play a role in the cellular and molecular mechanisms underlying glomerular injury. We investigated the potential role of NF-kappaB 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-kappaB subunits p65 and p50, and the NF-kappaB regulated proinflammatory mediators tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), 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-kappaB activation (both p65 and p50) was enhanced in glomerular endothelial, mesangial cells or infiltrating cells in class IV LN, along with upregulation of TNF-alpha, IL-1beta, IL-6 and ICAM-1 expression. Glomerular endothelial and mesangial activation of NF-kappaB and mesangial ICAM-1 expression correlated with disease activity and the level of glomerular macrophage infiltration. Podocyte NF-kappaB overactivation (predominantly p65) paralleled podocyte expression of TNF-alpha and IL-1beta in patients with LN and non-proliferative glomerulopathy. Podocyte staining scores of NF-kappaB and p65 were positively correlated with the severity of proteinuria in LN and non-proliferative glomerulopathy. These results suggest a pathogenic role for NF-kappaB in glomerular injury by multiple mechanisms.

The immunoexpression of glomerular NF-κB in proteinuric patients with proliferative and non-proliferative glomerulopathies

“…Contrary to us, Zheng et al showed a positive correlation of glomerular NF-κB also in the non-proliferative group. However, in this study glomerular NF-κB immunoexpression was confined only to podocytes [1]. Our observations may suggest different mechanisms of proteinuria in proliferative and non-proliferative glomerulopathies.…”

“…In the present study we revealed that glomerular immunoexpression of NF-κB was significantly increased in PG proteinuric patients as compared to the NPG group and controls. NF-κB activation has been observed in several experimental and human glomerular diseases [1,15,16]. Sakurai et al noted increased activation of NF-κB in rat glomeruli shortly after nephrotoxic serum administration and the development of proteinuria.…”

“…Transcription nuclear factor κB (NF-κB) is a pleiotropic transcription factor regulating the gene expression of several adhesion molecules, cytokines and chemotactic proteins involved in inflammation, immune response and cell proliferation [1][2][3]. It is a protein present as a homodimer or heterodimer of five members of the NF-κB/Rel family.…”

“…Immune complex formation and deposition in the kidney result in glomerular inflammation with recruitment of leukocytes, and the activation and proliferation of resident renal cells. However, cellular and molecular mechanisms underlying glomerular cell activation are not yet fully understood in human glomerulopathies [1]. Recent studies suggest that NF-κB activation plays an essential role in the activation of mesangial cells and macrophages through the transcriptional induction of inflammatory mediators of glomerular inflammation and injury [10,11].…”

NF-κB in Renal Inflammation

“…In general, NF-B activates in macrophages and glomerular (including podocytes in proteinuric diseases) and tubular parenchymal cells and correlates with parameters of severity of disease such as proteinuria or inflammation. 59,[61][62][63][64][65] These data have been interpreted as supportive for the role of NF-B in promoting inflammation; however, inflammation itself will promote NF-B activation, and because these data are descriptive, the precise role of the various NF-B complexes in human kidney injury remains uncertain. Functional evidence of NF-B activation has been obtained by transcriptomics-based pathway mapping 66 ; in progressive diabetic nephropathy, there is upregulation of 54 of 138 known NF-B targets with special enrichment in NF-B/IRFF module target genes.…”