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Interstitial Vascular Rarefaction and Reduced VEGF-A Expression in Human Diabetic Nephropathy

Maja T. Lindenmeyer^*, Matthias Kretzler^*,, Anissa Boucherot^*, Silvia Berra, Yoshinari Yasuda^*, Anna Henger, Felix Eichinger^*,, Stefanie Gaiser^*, Holger Schmid^*, Maria P. Rastaldi, Robert W. Schrier, Detlef Schlöndorff^* and Clemens D. Cohen^*

^* Nephrologisches Zentrum, Medizinische Poliklinik, University of Munich, Munich, Germany; Department of Medicine, University of Michigan, Ann Arbor, Michigan; Renal Immunopathology Laboratory, Fondazione D'Amico per la Ricerca sulle Malattie Renali, c/o San Carlo Borromeo Hospital, Milan, Italy; and Department of Medicine, University of Colorado, Denver, Colorado

Address correspondence to: Dr. Clemens D. Cohen, Nephrologisches Zentrum, Medizinische Poliklinik, University of Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany. Phone: +49-89-218075845; Fax: +49-89-218075860; E-mail: clemens.cohen{at}med.uni-muenchen.de

Received for publication December 1, 2006. Accepted for publication March 18, 2007.

Diabetic nephropathy (DN) is a frequent complication in patients with diabetes. Although the majority of DN models and human studies have focused on glomeruli, tubulointerstitial damage is a major feature of DN and an important predictor of renal dysfunction. This study sought to investigate molecular markers of pathogenic pathways in the renal interstitium of patients with DN. Microdissected tubulointerstitial compartments from biopsies with established DN and control kidneys were subjected to expression profiling. Analysis of candidate genes, potentially involved in DN on the basis of common hypotheses, identified 49 genes with significantly altered expression levels in established DN in comparison with controls. In contrast to some rodent models, the growth factors vascular endothelial growth factor A (VEGF-A) and epidermal growth factor (EGF) showed a decrease in mRNA expression in DN. This was validated on an independent cohort of patients with DN by real-time reverse transcriptase–PCR. Immunohistochemical staining for VEGF-A and EGF also showed a reduced expression in DN. The decrease of renal VEGF-A expression was associated with a reduction in peritubular capillary densities shown by platelet-endothelial cell adhesion molecule-1/CD31 staining. Furthermore, a significant inverse correlation between VEGF-A and proteinuria, as well as EGF and proteinuria, and a positive correlation between VEGF-A and hypoxia-inducible factor-1 mRNA was found. Thus, in human DN, a decrease of VEGF-A, rather than the reported increase as described in some rodent models, may contribute to the progressive disease. These findings and the questions about rodent models in DN raise a note of caution regarding the proposal to inhibit VEGF-A to prevent progression of DN.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673