title: Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy.
abstract: 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-1alpha 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.
authors.affiliation: Nephrologisches Zentrum, Medizinische Poliklinik, University of Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany.
authors.forename: Maja T
authors.initials: MT
authors.lastname: Lindenmeyer
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Anissa
authors.initials: A
authors.lastname: Boucherot
authors.forename: Silvia
authors.initials: S
authors.lastname: Berra
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Yasuda
authors.forename: Anna
authors.initials: A
authors.lastname: Henger
authors.forename: Felix
authors.initials: F
authors.lastname: Eichinger
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gaiser
authors.forename: Holger
authors.initials: H
authors.lastname: Schmid
authors.forename: Maria P
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schrier
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002196:Capillaries / Q000473:pathology / Q000502:physiology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007684:Kidney Tubules / Q000473:pathology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013045:Species Specificity; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004815:Epidermal Growth Factor