The accumulation of glomerular extracellular matrix proteins, especially fibronectin (FN), is a critical pathological characteristic of diabetic renal fibrosis. Inflammation mediated by nuclear factor-κB (NF-κB) plays a critical role in the pathogenesis of diabetic nephropathy (DN). RhoA/ROCK signaling is responsible for FN accumulation and NF-κB activation. Berberine (BBR) treatment significantly inhibited renal inflammation and thus improved renal damage in diabetes. Here, we study whether BBR inhibits FN accumulation and NF-κB activation by inhibiting RhoA/ROCK signaling and the underlying mechanisms involved. Results showed that BBR effectively inhibited RhoA/ROCK signaling activation in diabetic rat kidneys and high glucose-induced glomerular mesangial cells (GMCs) and simultaneously down-regulated NF-κB activity, which was accompanied by reduced intercellular adhesionmolecule-1, transforming growth factor-beta 1 and FN overproduction. Furthermore, we observed that BBR abrogated high glucose-mediated reactive oxygen species generation in GMCs. BBR and N-acetylcysteine inhibited RhoA/ROCK signaling activation in high glucose-exposed GMCs. Collectively, our data suggest that the renoprotective effect of BBR on DN partly depends on RhoA/ROCK inhibition. The anti-oxidative stress effect of BBR is responsible for RhoA/ROCK inhibition in DN.
Keywords: Berberine; DN; Diabetic nephropathy; ECM; Fibronectin; GMCs; ICAM-1; MDA; MYPT; N-acetylcysteine; NAC; NF-κB; ROCK; ROS; RhoA/ROCK; SOD; STZ; TGF-β1; diabetic nephropathy; extracellular matrix; glomerular mesangial cells; intercellular adhesionmolecule-1; malondialdehyde; myosin phosphatase; nuclear factor-kappa B; reactive oxygen species; rho kinase; streptozocin; superoxide dismutase; transforming growth factor-beta 1.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.