Abstract
Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM). This study aimed to explore the effects of corosolic acid (CA) on the renal damage of DM and the mechanisms behind these effects. The renoprotective effect of CA was investigated in type 1 diabetic rats and db/db mice. The kidneys and glomerular mesangial cells (GMCs) were used to study the proliferation of GMCs by immunostaining and MTT assay. Further immunoblotting, siRNA, qPCR analysis, and detecting of NADPH oxidase activity and reactive oxygen species (ROS) generation were performed to explore relevant molecular mechanisms. In CA-treated diabetic animals, diabetes-induced albuminuria, increased serum creatinine and blood urea nitrogen were significantly attenuated, and glomerular hypertrophy, mesangial expansion and fibrosis were ameliorated. Furthermore, CA significantly inhibited proliferation of GMCs and phosphorylation of ERK1/2 and p38 MAPK in both diabetic animals and high glucose (HG)-induced GMCs. CA also normalized Δψm and inhibited HG-induced NADPH oxidase activity, ROS generation and NOX4, NOX2, p22phox and p47phox expression. More importantly, CA inhibited GMC proliferation mediated by NADPH/ERK1/2 and p38 MAPK signaling pathways. These findings suggest that CA exert the protective effect on DN by anti-proliferation resulted from inhibition of p38 MAPK- and NADPH-mediated inactivation of ERK1/2.
Highlights
Glomerular mesangial cells (GMCs), one of the major constituents of the renal glomerulus, play important roles in mesangial matrix homeostasis, regulation of glomerular filtration rate, and phagocytosis of apoptotic cells in the glomerulus[17]
We provide the first evidence that CA blocks expression of NOX4, NOX2, and NOX-associated subunits p22phox and p47phox, inhibiting activation of ERK1/2 signal transduction, resulting in inhibition of GMC proliferation and thereby attenuating mesangial expansion in response to high glucose (HG). These results suggest that CA exert beneficial effects on Diabetic nephropathy (DN), and represent a novel mechanism of CA-mediated inhibition of HG-induced GMC proliferation
The effect of CA on the blood glucose of db/db mice are shown in Supplementary Fig. S1, the blood glucose were markedly increased in db/db mice compared with non-diabetic mice but were significantly improved with CA treatment
Summary
Glomerular mesangial cells (GMCs), one of the major constituents of the renal glomerulus, play important roles in mesangial matrix homeostasis, regulation of glomerular filtration rate, and phagocytosis of apoptotic cells in the glomerulus[17]. We found that CA downregulated MAPK activation, including phosphorylation of p38 MAPK and ERK1/2, leading to dose-dependent inhibition of proliferation of GMCs. In addition, we provide the first evidence that CA blocks expression of NOX4, NOX2, and NOX-associated subunits p22phox and p47phox, inhibiting activation of ERK1/2 signal transduction, resulting in inhibition of GMC proliferation and thereby attenuating mesangial expansion in response to HG. We provide the first evidence that CA blocks expression of NOX4, NOX2, and NOX-associated subunits p22phox and p47phox, inhibiting activation of ERK1/2 signal transduction, resulting in inhibition of GMC proliferation and thereby attenuating mesangial expansion in response to HG These results suggest that CA exert beneficial effects on DN, and represent a novel mechanism of CA-mediated inhibition of HG-induced GMC proliferation
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