Tubular NF-kappa B and AP-1 activation in human proteinuric renal disease

Mezzano, SA; Barria, M.; Droguett, MA; BURGOS, ME; Ardiles, LG; Flores C.; Egido, J

Abstract

Background: Nuclear factor-?B (NF-?B) and activated protein-1 (AP-1) are transcription factors that regulate many genes involved in the progression of renal disease. Recent data have shown that NF-?B is activated in tubules and glomeruli in various experimental models of renal injury. In vitro studies also suggest that proteinuria could be an important NF-?B activator. We therefore approached the idea that NF-?B may be an indicator of renal damage progression. Methods: Paraffin-embedded renal biopsy specimens from 34 patients with intense proteinuria [14 with minimal change disease (MCD) and 20 with idiopathic membranous nephropathy (MN)] and from 7 patients with minimal or no proteinuria (IgA nephropathy) were studied by Southwestern histochemistry for the in situ detection of activated transcription factors NF-?B and AP-1. In addition, by immunohistochemistry, we performed staining for the NF-?B subunits (p50 and p65) and AP-1 subunits (c-fos, c-jun). By immunohistochemistry and/or in situ hybridization, the expression of some chemokines [monocyte chemoattractant protein-1 (MCP-1), RANTES, osteopontin (OPN)] and profibrogenic cytokines [transforming growth factor-? (TGF-?)], whose genes are regulated by NF-?B and/or AP-1, were studied further. Results: NF-?B was detected mainly in the tubules of proteinuric patients, but rarely in nonproteinuric IgA nephropathy (IgAN) patients. In addition, there was a significant relationship between the intensity of proteinuria and NF-?B activation in MCD (r = 0.64, P = 0.01) and MN patients (r = 0.64, P<0.01). Unexpectedly, patients with MCD had a significantly higher NF-?B tubular activation than those with MN (P<0.01). To assess whether there was a different composition of NF-?B protein components, immunostaining was performed for the NF-?B subunits p50 and p65. However, no differences were noted between MCD and MN patients. In those patients, there was a lower tubular activation of AP-1 compared with NF-?B. Moreover, a strong correlation in the expression of both transcription factors was observed only in MN (r = 0.7, P = 0.004). Patients with progressive MN had an overexpression of MCP-1, RANTES, OPN, and TGF-?, mainly in the proximal tubules, while no significant expression was found in MCD patients. Conclusions: On the whole, our results show that a tubular overactivation of NF-?B and AP-1 and a simultaneous upregulation of certain proinflammatory and profibrogenic genes are markers of progressive renal disease in humans. Increased activation of solely NF-?B and/or AP-1 may merely indicate the response of tubular renal cells to injury.

Más información

Título según WOS: Tubular NF-kappa B and AP-1 activation in human proteinuric renal disease
Título según SCOPUS: Tubular NF-?B and AP-1 activation in human proteinuric renal disease
Título de la Revista: KIDNEY INTERNATIONAL
Volumen: 60
Número: 4
Editorial: Elsevier Science Inc.
Fecha de publicación: 2001
Página de inicio: 1366
Página final: 1377
Idioma: English
URL: http://www.nature.com/doifinder/10.1046/j.1523-1755.2001.00941.x
DOI:

10.1046/j.1523-1755.2001.00941.x

Notas: ISI, SCOPUS