Modular Activation of Nuclear Factor-κB Transcriptional Programs in Human Diabetic Nephropathy
- Holger Schmid1,
- Anissa Boucherot1,
- Yoshinari Yasuda1,
- Anna Henger1,
- Bodo Brunner2,
- Felix Eichinger1,
- Almut Nitsche2,
- Eva Kiss3,
- Markus Bleich4,
- Hermann-Josef Gröne3,
- Peter J. Nelson1,
- Detlef Schlöndorff1,
- Clemens D. Cohen1,
- Matthias Kretzler1 and
- for the European Renal cDNA Bank (ERCB) Consortium*
- 1Medizinische Poliklinik, University of Munich, Munich, Germany
- 2Sanofi-Aventis Deutschland, Frankfurt, Germany
- 3German Cancer Research Center, Heidelberg, Germany
- 4Physiology Institute, University of Kiel, Kiel, Germany
- Address correspondence and reprint requests to Clemens D. Cohen, MD, Division of Nephrology, Medizinische Poliklinik, University of Munich, Pettenkoferstr. 8a, 80336 Munich, Germany. E-mail: clemens.cohen{at}med.uni-muenchen.de
- Matthias Kretzler, MD, Division of Nephrology, University of Michigan, 1570 MSRB II, 1150 W. Medical Ctr. Dr., Ann Arbor, MI 48109-0676. E-mail: kretzler{at}umich.edu
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-κB (NF-κB), a master transcriptional switch in inflammation, segregated progressive from mild DN and control subjects by showing upregulation of 54 of 138 known NF-κB targets. The promoter regions of regulated NF-κB targets were analyzed using ModelInspector, and the NF-κB 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-κB 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.
- CD, cadaveric donor
- DN, diabetic nephropathy
- FDR, false discovery rate
- IRF, interferon regulatory factor
- LD, living donor
- MCD, minimal change disease
- NF-κB, nuclear factor-κB
- RMA, robust multichip analysis
- SAM, Significance Analysis of Microarrays
Footnotes
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* A complete list of the members of the European Renal cDNA Bank Consortium can be found in the appendix.
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H.S., A.B., and Y.Y. contributed equally to this work.
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A.B. is currently affiliated with Sanofi-Aventis Deutschland, Frankfurt, Germany.
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A.H., F.E., and M.K. are currently affiliated with the Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted August 3, 2006.
- Received April 11, 2006.
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