NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy.
BACKGROUND
Nuclear factor-kappaB (NF-kappaB) regulates genes involved in renal disease progression, such as the chemokines monocyte chemoattractant protein-1 (MCP-1) and RANTES. NF-kappaB is activated in experimental models of renal injury, and in vitro studies also suggest that proteinuria and angiotensin II could be important NF-kappaB activators. It has been proposed that locally produced MCP-1 may be involved in the development of diabetic nephropathy (DN). We examined the hypothesis that NF-kappaB could be an indicator of renal damage progression in DN.


METHODS
Biopsy specimens from 11 patients with type 2 diabeties and overt nephropathy were studied by southwestern histochemistry for the in situ detection of activated NF-kappaB. In addition, by immunohistochemistry and/or in situ hybridization, we studied the expression of MCP-1 and RANTES, whose genes are regulated by NF-kappaB.


RESULTS
NF-kappaB was detected mainly in cortical tubular epithelial cells and, to a lesser extent, in some glomerular and interstitial cells. A strong upregulation of MCP-1 and RANTES was observed in all the cases, mainly in tubular cells, and there was a strong correlation between the expression of these chemokines and NF-kappaB activation in the same cells, as observed in serial sections (r = 0.7; P = 0.01). In addition, the tubular expression of these chemokines was correlated mainly with the magnitude of the proteinuria (P = 0.002) and with interstitial cell infiltration (P<0.05).


CONCLUSIONS
The activation of NF-kappaB and the transcription of certain pro-inflammatory chemokines in tubular epithelial cells are markers of progressive DN. Proteinuria might be one of the main factors inducing the observed pro-inflammatory phenotype.
Department of Nephrology, School of Medicine, Universidad Austral Bueras 1003 2 P, PO Box 8-D, Valdivia, Chile. smezzano@uach.cl
Sergio
S
Mezzano
Claudio
C
Aros
Alejandra
A
Droguett
M Eugenia
ME
Burgos
Leopoldo
L
Ardiles
Claudio
C
Flores
Herman
H
Schneider
Marta
M
Ruiz-Ortega
Jesús
J
Egido
D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger / Q000378:metabolism; D051996:Transcription Factor RelA; D015854:Up-Regulation
D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D051996:Transcription Factor RelA