Matrix Protein Production in Diabetes Complications Studied

miR-146a found to aid in the transcriptional circuitry regulating extracellular matrix protein production

MONDAY, Sept. 12 (HealthDay News) -- Glucose-induced extracellular matrix protein fibronectin (FN) upregulation in endothelial cells and in the retina of diabetic rats is mediated through microR-146a (miR-146a), according to an experimental study published online Sept. 1 in Diabetes.

Biao Feng, from the Schulich School of Medicine and Dentistry in London, Canada, and colleagues investigated the role of miR-146a on FN production in diabetes, and its relationship with p300. Expression of miR-146a was assessed at various glucose levels in the endothelial cells from large vessels and retinal microvessels. FN messenger RNA expression was estimated along with protein levels, with or without miR-146a mimic or antagomir transfection. miR-146a binding to FN 3'untranslated region (UTR) was detected by luciferase assay. Retinas from rats with type 1 diabetes with or without miR-146a mimic intravitreal injection were examined, and retinal miR-146a was localized by in situ hybridization. Cardiac and renal tissues from type 1 and 2 diabetic animals were examined.

The investigators found that compared to 5 mmol/L glucose, 25 mmol/L glucose decreased miR-146a expression, and increased FN expression in both cell types. This change was prevented by miR-146a mimic transfection. In cells in 5 mmol/L glucose, miR-146a antagomir transfection resulted in FN upregulation. The miR-146a binding to FN 3'-UTR was confirmed by luciferase assay. The miR-146a localized in retinal endothelial cells and was reduced in diabetes. The retinal miR-146a was restored, and FN was increased in diabetes by intravitreal miR-146a injection. The miR-146a was regulated by p300. Retinas, kidneys, and hearts from type 1 and 2 diabetic animals yielded similar results.

"These studies showed a novel, glucose-induced molecular mechanism in which miR-146a participates in the transcriptional circuitry regulating extracellular matrix protein production in diabetes," the authors write.

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