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This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2006010064v1 17/11/3093    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sung, S. H. Articles by Chen, S. Search for Related Content PubMed PubMed Citation Articles by Sung, S. H. Articles by Chen, S. Related Collections Related Articles

Blockade of Vascular Endothelial Growth Factor Signaling Ameliorates Diabetic Albuminuria in Mice

Sun Hee Sung^*,, Fuad N. Ziyadeh^*,, Amy Wang, Petr E. Pyagay, Yashpal S. Kanwar^|| and Sheldon Chen

^* Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pathology, Ewha Women’s University, Mok Dong Hospital, Seoul, Korea; Faculty of Medicine, American University of Beirut, Beirut, Lebanon; and Division of Nephrology/Hypertension and ^|| Department of Pathology, Northwestern University, Chicago, Illinois

Address correspondence to: Dr. Sheldon Chen, Northwestern University, Searle 10-475, 320 E. Superior Street, Chicago, IL 60611. Phone: 312-503-6880; Fax: 312-503-0622; E-mail: sheldon-chen{at}northwestern.edu

Received for publication January 22, 2006. Accepted for publication August 5, 2006.

For investigation of how the vascular endothelial growth factor (VEGF) system participates in the pathogenesis of diabetic kidney disease, type 2 diabetic db/db and control db/m mice were treated intraperitoneally with vehicle or 2 mg/kg of a pan-VEGF receptor tyrosine kinase inhibitor, SU5416, twice a week for 8 wk. Efficacy of SU5416 treatment in the kidney was verified by the inhibition of VEGF receptor-1 phosphorylation. Glomerular VEGF immunostaining, normally increased in diabetes, was unaffected by SU5416. Plasma creatinine did not change with diabetes or SU5416 treatment. The primary end point of albuminuria increased approximately four-fold in the diabetic db/db mice but was significantly ameliorated by SU5416. Correlates of albuminuria were investigated. Diabetic glomerular basement membrane thickening was prevented in the SU5416-treated db/db mice, whereas mesangial matrix expansion remained unchanged by treatment. The density of open slit pores between podocyte foot processes was decreased in db/db diabetes but was partly increased toward normal by SU5416. Finally, nephrin protein by immunofluorescence was decreased in the db/db mice but was significantly restored by SU5416. Paradoxically, total nephrin protein by immunoblotting was increased in diabetes, pointing toward a possible dysregulation of nephrin trafficking. Diabetic albuminuria is partially a function of VEGF receptor signaling overactivity. VEGF signaling was found to affect a number of podocyte-driven manifestations such as GBM thickening, slit pore density, and nephrin quantity, all of which are associated with the extent of diabetic albuminuria. By impeding these pathophysiologic processes, VEGF receptor inhibition by SU5416 might become a useful adjunct to anti-albuminuria therapy in diabetic nephropathy.

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