Journal
AMERICAN JOURNAL OF NEPHROLOGY
Volume 30, Issue 4, Pages 336-345Publisher
KARGER
DOI: 10.1159/000227762
Keywords
Advanced glycation end products; Podocytes; Neuropilin-1 promoter; Diabetic nephropathy
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Funding
- Deutsche Forschungsgemeinschaft [Wo 460/14-1, 14-2]
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Background: Neuropilin-1 (NRP1) is a transmembrane glycoprotein, initially defined as a receptor for members of the semaphorin family. We observed that NRP1 expression was downregulated by the addition of advanced glycation end products-modified bovine serum albumin (AGE-BSA). The present study was undertaken to unravel the molecular mechanisms underlying AGE-BSA-mediated NRP1 suppression. Methods: Expression of NRP1 was analyzed in podocytes. The transcriptional activity of the NRP1 promoter was investigated using wild-type and mutant NRP1 promoter reporter constructs. Electrophoretic mobility assays were performed. Results: NRP1 expression was downregulated in podocytes by the addition of AGE-BSA. In contrast, phorbolester induced NRP1 mRNA and protein expression. The wild-type promoter transcriptional activity was significantly reduced when podocytes were treated with AGE-BSA compared with control, unmodified BSA. Point mutations of proximal and distal Sp1-like sites inhibited basal NRP1 promoter activity. AGE-BSA failed to further suppress transcriptional activity of these constructs. Double mutation of the Sp1A and Sp1B binding sites completely abolished NRP1 transcriptional activity. Gel shift analysis showed a specific binding of the Sp1 transcription factor. Treatment of podocytes with AGE-BSA revealed a decrease in Sp1 binding to consensus sequences, but no effect on AP1 binding. Conclusions: AGE-BSA inhibits NRP1 promoter transcriptional activity in podocytes by reducing the binding ability of the Sp1 transcription factor to attach to the NRP1 promoter. Copyright (C) 2009 S. Karger AG, Basel
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