PMID- 11576350
OWN - NLM
STAT- MEDLINE
DCOM- 20020103
LR  - 20220409
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 60
IP  - 4
DP  - 2001 Oct
TI  - Tubular NF-kappaB and AP-1 activation in human proteinuric renal disease.
PG  - 1366-77
AB  - BACKGROUND: Nuclear factor-kappaB (NF-kappaB) 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-kappaB 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-kappaB activator. We therefore 
      approached the idea that NF-kappaB 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-kappaB and AP-1. In 
      addition, by immunohistochemistry, we performed staining for the NF-kappaB 
      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-beta (TGF-beta)], whose genes are regulated 
      by NF-kappaB and/or AP-1, were studied further. RESULTS: NF-kappaB 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-kappaB 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-kappaB tubular activation than those with MN (P < 
      0.01). To assess whether there was a different composition of NF-kappaB protein 
      components, immunostaining was performed for the NF-kappaB 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-kappaB. 
      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-beta, 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-kappaB and 
      AP-1 and a simultaneous up-regulation of certain proinflammatory and 
      profibrogenic genes are markers of progressive renal disease in humans. Increased 
      activation of solely NF-kappaB and/or AP-1 may merely indicate the response of 
      tubular renal cells to injury.
FAU - Mezzano, S A
AU  - Mezzano SA
AD  - Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile. 
      smezzano@uach.cl
FAU - Barria, M
AU  - Barria M
FAU - Droguett, M A
AU  - Droguett MA
FAU - Burgos, M E
AU  - Burgos ME
FAU - Ardiles, L G
AU  - Ardiles LG
FAU - Flores, C
AU  - Flores C
FAU - Egido, J
AU  - Egido J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Chemokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (NF-kappa B)
RN  - 0 (Transcription Factor AP-1)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Chemokines/metabolism
MH  - Child
MH  - Child, Preschool
MH  - Female
MH  - Glomerulonephritis, Membranous/*physiopathology/urine
MH  - Histocytochemistry
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Hybridization
MH  - Inflammation Mediators/metabolism
MH  - Kidney Tubules/*metabolism
MH  - Male
MH  - NF-kappa B/*physiology
MH  - Nephrosis, Lipoid/*physiopathology/urine
MH  - Proteinuria/etiology
MH  - Reference Values
MH  - Transcription Factor AP-1/*physiology
EDAT- 2001/09/29 10:00
MHDA- 2002/01/05 10:01
CRDT- 2001/09/29 10:00
PHST- 2001/09/29 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/09/29 10:00 [entrez]
AID - S0085-2538(15)48004-4 [pii]
AID - 10.1046/j.1523-1755.2001.00941.x [doi]
PST - ppublish
SO  - Kidney Int. 2001 Oct;60(4):1366-77. doi: 10.1046/j.1523-1755.2001.00941.x.