Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy.
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.
Schmid
Holger
H
Division of Nephrology, Medizinische Poliklinik, University of Munich, Pettenkoferstr. 8a, 80336 Munich, Germany.
Boucherot
Anissa
A
Yasuda
Yoshinari
Y
Henger
Anna
A
Brunner
Bodo
B
Eichinger
Felix
F
Nitsche
Almut
A
Kiss
Eva
E
Bleich
Markus
M
Gröne
Hermann-Josef
HJ
Nelson
Peter J
PJ
Schlöndorff
Detlef
D
Cohen
Clemens D
CD
Kretzler
Matthias
M
D001706:Biopsy; D002102:Cadaver; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D007668:Kidney / Q000166:cytology / Q000473:pathology; D019520:Living Donors; D016328:NF-kappa B / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D014019:Tissue Donors; D014158:Transcription, Genetic
D016328:NF-kappa B; D012333:RNA, Messenger