NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy

Nephrol Dial Transplant. 2004 Oct;19(10):2505-12. doi: 10.1093/ndt/gfh207. Epub 2004 Jul 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / metabolism
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism*
  • Chemokine CCL5 / genetics
  • Chemokine CCL5 / metabolism*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology
  • Disease Progression
  • Female
  • Gene Expression
  • Gene Expression Regulation
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Inflammation / pathology
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Middle Aged
  • NF-kappa B / metabolism*
  • NF-kappa B p50 Subunit
  • RNA, Messenger / metabolism
  • Transcription Factor RelA
  • Up-Regulation


  • Biomarkers
  • CCL2 protein, human
  • Chemokine CCL2
  • Chemokine CCL5
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • RNA, Messenger
  • Transcription Factor RelA