Spleen tyrosine kinase mediates high glucose-induced transforming growth factor-β1 up-regulation in proximal tubular epithelial cells

The role of spleen tyrosine kinase (Syk) in high glucose-induced intracellular signal transduction has yet to be elucidated. We investigated whether Syk is implicated in high glucose-induced transforming growth factor-ill (TGF-beta 1) up-regulation in cultured human proximal tubular epithelial cells (HK-2 cell). High glucose increased TGF-beta 1 gene expression through Syk, extracellular signal-regulated kinase (ERK), AP-1 and NF-kappa B. High glucose-induced AP-1 DNA binding activity was decreased by Syk inhibitors and U0126 (an ERK inhibitor). Syk inhibitors suppressed high glucose-induced ERK activation, whereas U0126 had no effect on Syk activation. High glucose-induced NF-kappa B DNA binding activity was also decreased by Syk inhibitors. High glucose increased nuclear translocation of p65 without serine phosphorylation of I kappa B alpha and without degradation of I kappa B alpha, but with an increase in tyrosine phosphorylation of I kappa B alpha that may account for the activation of NF-kappa B. Both Syk inhibitors and Syk-siRNA attenuated high glucose-induced I kappa B alpha tyrosine phosphorylation and p65 nuclear translocation. Depletion of p21-activated kinase 2 (Pak2) by transfection of Pak2-siRNA abolished high glucose-induced Syk activation. In summary, high glucose-induced TGF-beta 1 gene transcription occurred through Pak2, Syk and subsequent ERK/AP-1 and NF-kappa B pathways. This suggests that Syk might be implicated in the diabetic kidney disease. (C) 2012 Elsevier Inc. All rights reserved.