Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 369, Issue 1-2, Pages 86-97Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2013.01.007
Keywords
Diabetic nephropathy; RhoA/ROCK; NF-kappa B; Fibronectin; Fasudil
Categories
Funding
- National Natural Science Foundation of China [81170676]
- Science, Technology Program of Guangdong Province, PR China [2011A080502004]
- Guangzhou Science and Technology Project [10A32060084]
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Both RhoA/ROCK and NF-kappa B signaling pathways play important roles in the pathogenesis of diabetic nephropathy (DN). However, it remains unknown whether and how RhoA/ROCK regulates NF-kappa B signaling in diabetic kidneys. In cultured glomerular mesangial cells (GMCs), the high glucose-activated NF-kappa B nuclear translocation and DNA binding activity were attenuated by ROCK inhibitor Y27632 or dominant-negative RhoA mutant, indicating that RhoA/ROCK signaling regulates high glucose-activated NF-kappa B pathway. Furthermore, NF-kappa B-regulated inflammatory factors ICAM-1 and TGF-beta 1 were markedly increased in high glucose-treated GMCs, leading to accumulation of fibronectin (FN), an important component of extracellular matrix (ECM), This effect was also effectively attenuated by Y27632 or dominant-negative RhoA mutant. In STZ-induced diabetic rats, treatment with ROCK inhibitor fasudil suppressed the RhoA/ROCK activation and NF-kappa B nuclear translocation, and significantly reduced the renal FN, ICAM-1 and TGF-beta 1 protein levels. Thus, the RhoA/ROCK pathway may regulate NF-kappa B to upregulate inflammatory genes and mediate the development of DN. (c) 2013 Elsevier Ireland Ltd. All rights reserved.
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