Pathogenic Role of NF-κB Activation in Tubulointerstitial Inflammatory Lesions in Human Lupus Nephritis

Abstract

(RS) S U M M A R Y In vitro and in vivo experimental studies suggest that the transcription factor NF-kB plays a role in tubulointerstitial injury. We investigated possible cellular and molecular mechanisms involving NF-kB activation in the progression of tubulointerstitial lesions in human lupus nephritis (LN). Paraffin-embedded renal biopsies from 50 patients with LN and six control patients with minimal change disease (MCD) were examined by Southwestern histochemistry for in situ detection of active NF-kB and AP-1. Immunohistochemistry was performed to examine the expression of NF-kB, AP-1, and NF-kB regulatory proteins (IkB-a, p-IkB-a, and IKK-a proteins), as well as NF-kB and AP-1 downstream target proinflammatory molecules (ICAM-1, TNF-a, IL-1b, IL-6, and GM-CSF) and NF-kB upstream signaling molecules (CD40 and CD40L). We observed extensive upregulation of activated NF-kB in renal tubular cells and interstitial cells, in parallel with overactivation of transcription factor AP-1 in LN, as compared with normal controls and MCD. Tubular expression of activated NF-kB correlated well with the degree of tubulointerstitial histopathological indices and/or renal function. Tubulointerstitial IKK-a expression was specifically upregulated in LN. IkB-a and p-IkB-a were detected only in interstitial cells in LN. Tubulointerstitial expression levels of NF-kB and AP-1 downstream inflammatory molecules and NF-kB upstream signaling molecules CD40 and CD40L were markedly enhanced in LN as compared with MCD or normal controls and were associated with tubulointerstitial histopathological indices and/or renal function. The results suggest that altered IKK-a expression and NF-kB activation along with AP-1 overexpression may play a pathogenic role in tubulointerstitial injury in human LN mediated through a network of downstream proinflammatory molecules. (J Histochem Cytochem 56:517-529, 2008)

Tubular NF-κB is overexpressed in proteinuric patients with IgA nephropathy

“…The mechanisms by which proteinuria could cause interstitial inflammation and fibrosis are still not fully understood [19,26]. NF-kB activation in renal tubular cells has been implicated in tubulointerstitial injury in proteinuriainduced rat models [23,27] and has been suggested to play a role in tubulointerstitial injury in human membranous glomerulopathy, IgA nephropathy, lupus nephritis, minimal change disease and diabetic nephropathy [9,19,28,29]. The results of our present study support these suggestions.…”

“…Moreover, the immunoexpression of NF-kB correlated positively with interstitial infiltrations of CD68 + cells, in proteinuric individuals significantly. A similar relationship was observed by Zheng et al in human lupus nephritis [9]. Monocytes/macrophages are believed to be involved in an interplay through a network of inflammatory mediators, which is crucial for the progression of tubulointerstitial injury [14].…”

“…Extensive upregulation of NF-kB in renal tubular cells has also been observed in lupus nephritis, as compared with normal controls and minimal change disease [9]. Moreover, it has been noted that NF-kB is activated in tubules in various experimental models of renal injury with protein-overload proteinuria [23,24].…”

“…When activated by cytokines, mitogens, viruses or cell injury it moves to the nucleus, binds DNA and influences the transcription of specific genes involved in inflammation, such as cytokines and adhesion molecules; hence, it is present in a variety of chronic inflammatory disorders [5,6]. Increasing data also suggests that NF-kB plays a pivotal role in many glomerulopathies [7,8], especially immune-mediated with prominent tubulointerstitial injury [9,10]. It has also been shown that high albumin concentration may induce NF-kB activation and in the process tubular injury in proteinuric states [1,11,12].…”

“…It has also been shown that high albumin concentration may induce NF-kB activation and in the process tubular injury in proteinuric states [1,11,12]. On the other hand, tubular epithelial cells are known to play a central role in initiating and amplifying tubulointerstitial inflammation via cross-talk with inflammatory cells by the production of a variety of inflammatory mediators [9,13,14].…”