CK2 alpha promotes advanced glycation end products-induced expressions of fibronectin and intercellular adhesion molecule-1 via activating MRTF-A in glomerular mesangial cells

摘要

Advanced glycation end products' (AGES) modification of extracellular matrix proteins induces crosslinking, which results in thickening of the basement membrane and activating several intracellular signaling cascades, eventually promoting the pathological progression of diabetic nephropathy (DN). We have previously confirmed that casein kinase 2 alpha(CK2 alpha) activates the nuclear factor of kappaB (NF-kappa B) signaling pathway to enhance high glucose-induced expressions of fibronectin (FN) and intercellular adhesion molecule-1 (ICAM-1) in glomerular mesangial cells (GMCs). However, to date, the mechanism by which CK2 alpha regulates diabetic renal fibrosis is not fully understood. In view of the regulation of inflammation and fibrosis by myocardin-related transcription factor A (MRTF-A), we are highly concerned whether CK2 alpha promotes AGEs-induced expressions of FN and ICAM-1 in glomerular mesangial cells via activation of MRTF-A, thus affecting the pathogenesis of DN. We found that CK2 alpha and MRTF-A proteins were over expressed in AGEs-induced diabetic kidneys. Inhibition of CK2 alpha kinase activity or knockdown of CK2 alpha protein expression suppressed the upregulation of FN and ICAM-1 expressions in GMCs induced by AGEs. MRTF-A knockdown compromised the expressions of FN and ICAM-1 in GMCs induced by AGEs. Moreover, inhibition of CK2 alpha kinase activity or knockdown of CK2 alpha protein expression restrained the protein expression and nuclear aggregation of MRTF-A. ClU alpha interacted with MRTF-A. Furthermore, knockdown of MRTF-A while overexpression of CK2 alpha blocked the upregulation effect of CK2 alpha on the protein expressions of FN and ICAM-1. These findings suggest that CK2 alpha promotes diabetic renal fibrosis via activation of MRTF-A and upregulation of inflammatory genes. (C) 2017 Elsevier Inc. All rights reserved.