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Comparative Study
. 2006 Nov;55(11):2993-3003.
doi: 10.2337/db06-0477.

Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy

Holger Schmid  1 , Anissa Boucherot, Yoshinari Yasuda, Anna Henger, Bodo Brunner, Felix Eichinger, Almut Nitsche, Eva Kiss, Markus Bleich, Hermann-Josef Gröne, Peter J Nelson, Detlef Schlöndorff, Clemens D Cohen, Matthias Kretzler; European Renal cDNA Bank (ERCB) Consortium
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Comparative Study

Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy

Holger Schmid et al. Diabetes. 2006 Nov.

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal failure and a major risk factor for cardiovascular mortality in diabetic patients. To evaluate the multiple pathogenetic factors implicated in DN, unbiased mRNA expression screening of tubulointerstitial compartments of human renal biopsies was combined with hypothesis-driven pathway analysis. Expression fingerprints obtained from biopsies with histological diagnosis of DN (n = 13) and from control subjects (pretransplant kidney donors [n = 7] and minimal change disease [n = 4]) allowed us to segregate the biopsies by disease state and stage by the specific expression signatures. Functional categorization showed regulation of genes linked to inflammation in progressive DN. Pathway mapping of nuclear factor-kappaB (NF-kappaB), a master transcriptional switch in inflammation, segregated progressive from mild DN and control subjects by showing upregulation of 54 of 138 known NF-kappaB _targets. The promoter regions of regulated NF-kappaB _targets were analyzed using ModelInspector, and the NF-kappaB module NFKB_IRFF_01 was found to be specifically enriched in progressive disease. Using this module, the induction of eight NFKB_IRFF_01-dependant genes was correctly predicted in progressive DN (B2M, CCL5/RANTES, CXCL10/IP10, EDN1, HLA-A, HLA-B, IFNB1, and VCAM1). The identification of a specific NF-kappaB promoter module activated in the inflammatory stress response of progressive DN has helped to characterize upstream pathways as potential _targets for the treatment of progressive renal diseases such as DN.

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