Abstract
Vascular endothelial growth factor (VEGF) is a dimeric glycoprotein that plays a crucial role in microvascular complications of diabetes, including diabetic nephropathy. However, the precise regulatory mechanisms governing VEGF expression in the diabetic milieu are still poorly understood. Here, we provide evidence that microRNA-93 (miR-93) regulates VEGF expression in experimental models of diabetes both in vitro and in vivo. Comparative microRNA expression profile arrays identified miR-93 as a signature microRNA in hyperglycemic conditions. We identified VEGF-A as a putative target of miR-93 in the kidney with a perfect complementarity between miR-93 and the 3'-untranslated region of vegfa in several species. When cotransfected with a luciferase reporter construct containing the mouse vegfa 3'-untranslated region, expression of miR-93 markedly decreased the luciferase activity. We showed that forced expression of miR-93 in cells abrogated VEGF protein secretion. Conversely, anti-miR-93 inhibitors increased VEGF release. Transfection of miR-93 also prevented the effect of high glucose on VEGF downstream targets. Using transgenic mice containing VEGF-LacZ bicistronic transcripts, we found that inhibition of glomerular miR-93 by peptide-conjugated morpholino oligomers elicited increased expression of VEGF. Our findings also indicate that high glucose decreases miR-93 expression by down-regulating the promoter of the host MCM7 gene. Taken together, our findings provide new insights into the role of miR-93 in VEGF signaling pathway and offer a potentially novel target in preventing the progression of diabetic nephropathy.
Highlights
Grants R01DK067604 and R01DK078900 through the NIDDK. □S The on-line version of this article contains supplemental Tables 1– 4. 1 Both authors contributed to this work. 2 To whom correspondence should be addressed: Division of Nephrology, Dept. of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030
Hyperglycemia Elicits Down-regulation of miR-93 Expression—Comparative miRNA arrays from high glucose-exposed (25 mM) podocytes and kidney microvascular endothelial cells, as well as in the kidney glomeruli obtained from diabetic db/db mice revealed that a number of miRNAs were differentially modulated in high glucose conditions (Fig. 1 and supplemental Tables 1– 4)
Because we were interested in the role of miRNAs on the expression of Vascular endothelial growth factor (VEGF)-A in the diabetic environment, we initially focused on miRNAs that were preferentially down-regulated under hyperglycemic conditions
Summary
Grants R01DK067604 and R01DK078900 through the NIDDK. □S The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1– 4. 1 Both authors contributed to this work. 2 To whom correspondence should be addressed: Division of Nephrology, Dept. of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Hyperglycemia Elicits Down-regulation of miR-93 Expression—Comparative miRNA arrays from high glucose-exposed (25 mM) podocytes and kidney microvascular endothelial cells, as well as in the kidney glomeruli obtained from diabetic db/db mice revealed that a number of miRNAs were differentially modulated in high glucose conditions (Fig. 1 and supplemental Tables 1– 4).
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