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

Background. Nuclear factor-kB (NF-kB) regulates genes involved in renal disease progression, such as the chemokines monocyte chemoattractant protein-1 (MCP-1) and RANTES. NF-kB is activated in experimental models of renal injury, and in vitro studies also suggest that proteinuria and angiotensin II could be important NF-kB 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-kB 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-kB. In addition, by immunohistochemistry and/or in situ hybridization, we studied the expression of MCP-1 and RANTES, whose genes are regulated by NF-kB. Results. NF-kB 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-kB activation in the same cells, as observed in serial sections (r1⁄4 0.7; P1⁄4 0.01). In addition, the tubular expression of these chemokines was correlated mainly with the magnitude of the proteinuria (P1⁄4 0.002) and with interstitial cell infiltration (P<0.05). Conclusions. The activation of NF-kB 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.