Modular Activation of Nuclear Factor-κB Transcriptional Programs in Human Diabetic Nephropathy

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 11; pp. 2993 - 3003
• Main Authors: SCHMID, Holger, BOUCHEROT, Anissa, NELSON, Peter J, SCHLÖNDORFF, Detlef, COHEN, Clemens D, KRETZLER, Matthias, YASUDA, Yoshinari, HENGER, Anna, BRUNNER, Bodo, EICHINGER, Felix, NITSCHE, Almut, KISS, Eva, BLEICH, Markus, GRÖNE, Hermann-Josef
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.11.2006
• Subjects: Biological and medical sciences; Care and treatment; Diabetes. Impaired glucose tolerance; Diabetic nephropathies; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Kidneys; Medical sciences; Nephrology. Urinary tract diseases; Risk factors; Urinary system involvement in other diseases. Miscellaneous; Germany; Endocrinopathy; Kidney disease; Human; Diabetic nephropathy; Urinary system disease; Diabetes mellitus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-0477

Modular Activation of Nuclear Factor-κB Transcriptional Programs in Human Diabetic Nephropathy Holger Schmid 1 , Anissa Boucherot 1 , Yoshinari Yasuda 1 , Anna Henger 1 , Bodo Brunner 2 , Felix Eichinger 1 , Almut Nitsche 2 , Eva Kiss 3 , Markus Bleich 4 , Hermann-Josef Gröne 3 , Peter J. Nelson 1 , Detlef Schlöndorff 1 , Clemens D. Cohen 1 , Matthias Kretzler 1 and for the European Renal cDNA Bank (ERCB) Consortium * 1 Medizinische Poliklinik, University of Munich, Munich, Germany 2 Sanofi-Aventis Deutschland, Frankfurt, Germany 3 German Cancer Research Center, Heidelberg, Germany 4 Physiology 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 * * A complete list of the members of the European Renal cDNA Bank Consortium can be found in the appendix . H.S., A.B., and Y.Y. contributed equally to this work. A.B. is currently affiliated with Sanofi-Aventis Deutschland, Frankfurt, Germany. A.H., F.E., and M.K. are currently affiliated with the Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . 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. Accepted August 3, 2006. Received April 11, 2006. DIABETES