HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Online-Only Appendix Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schmid, H. Search for Related Content PubMed PubMed Citation Articles by Schmid, H. Social Bookmarking                What's this?

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

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

Abbreviations: CD, cadaveric donor; DN, diabetic nephropathy; FDR, false discovery rate; IRF, interferon regulatory factor; LD, living donor; MCD, minimal change disease; NF-B, nuclear factor-B; RMA, robust multichip analysis; SAM, Significance Analysis of Microarrays

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-B (NF-B), a master transcriptional switch in inflammation, segregated progressive from mild DN and control subjects by showing upregulation of 54 of 138 known NF-B targets. The promoter regions of regulated NF-B targets were analyzed using ModelInspector, and the NF-B 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-B 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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Qian, E. Feldman, S. Pennathur, M. Kretzler, and F. C. Brosius III From Fibrosis to Sclerosis: Mechanisms of Glomerulosclerosis in Diabetic Nephropathy Diabetes, June 1, 2008; 57(6): 1439 - 1445. [Full Text] [PDF]

				H. Kato, H. Si, T. Hostetter, and K. Susztak Smad1 as a Biomarker for Diabetic Nephropathy Diabetes, June 1, 2008; 57(6): 1459 - 1460. [Full Text] [PDF]

				S. K. Cordovado, Y. Zhao, J. H. Warram, H. Gong, K. L. Anderson, M. M. Hendrix, L. N. Hancock, P. A. Cleary, and P. W. Mueller Nephropathy in Type 1 Diabetes Is Diminished in Carriers of HLA-DRB1*04: The Genetics of Kidneys in Diabetes (GoKinD) Study Diabetes, February 1, 2008; 57(2): 518 - 522. [Abstract] [Full Text] [PDF]

				C. Temm and J. H. Dominguez Microcirculation: nexus of comorbidities in diabetes Am J Physiol Renal Physiol, August 1, 2007; 293(2): F486 - F493. [Abstract] [Full Text] [PDF]

				M. T. Lindenmeyer, M. Kretzler, A. Boucherot, S. Berra, Y. Yasuda, A. Henger, F. Eichinger, S. Gaiser, H. Schmid, M. P. Rastaldi, et al. Interstitial Vascular Rarefaction and Reduced VEGF-A Expression in Human Diabetic Nephropathy J. Am. Soc. Nephrol., June 1, 2007; 18(6): 1765 - 1776. [Abstract] [Full Text] [PDF]