ERK5 Regulates glucose-induced increased fibronectin production in the endothelial cells and in the retina in diabetes.

Invest Ophthalmol Vis Sci. 2012 Dec 19;53(13):8405-13.

Wu Y, Feng B, Chen S, Chakrabarti S.

Department of Pathology, University of Western Ontario, Schulich School of Medicine, London, Ontario, Canada.



PURPOSE: Fibronectin (FN) production and deposition in the tissue is a characteristic feature of diabetic retinopathy. ERK5 is a recent member of the mitogen activated protein kinase (MAPK) family, which plays a critical role in cardiovascular development and maintaining endothelial cell integrity. The aim of this study was to investigate the role of ERK5 signaling in glucose-induced FN overproduction.

METHODS: Dermal-derived human microvascular endothelial cells (HMVECs) and human retinal microvascular endothelial cells (HRMECs) were used in this study. FN mRNA levels and secreted FN protein levels were measured using real-time PCR and ELISA, respectively. Constitutively active MAPK/ERK kinase 5 (MEK5 [CAMEK5]) adenovirus was used to upregulate ERK5. Dominant negative MEK5 (DNMEK5) and ERK5 siRNA (siERK5) were used to downregulate ERK5. Parallel retinal tissues of diabetic rats were examined.

RESULTS: A significant decrease of FN was observed at both protein and mRNA levels following CAMEK5 transduction in basal as well as in high glucose. DNMEK5 transduction led to further enhancement of glucose-induced increased FN expression. siERK5 treatment led to an increase of FN synthesis. Retinal tissues of diabetic rats showed FN upregulation and ERK5 downregulation. TGFβ1 mRNA and phosphorylated Smad2 were markedly suppressed by CAMEK5 transduction with and without glucose treatment. On the other hand, siERK5 transfection enhanced TGFβ1 mRNA expression. Exogenous nerve growth factor supplementation resulted in elevated phosphorylated and total ERK5 with and without glucose treatment.

CONCLUSIONS: Our experiments demonstrated a novel mechanism of glucose-induced increased FN production in diabetic retinopathy, which is mediated through decreased ERK5 signaling.

PMID: 23188731


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