期刊
MOLECULAR AND CELLULAR ENDOCRINOLOGY
卷 405, 期 C, 页码 74-83出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2015.02.007
关键词
GA; Tubulointerstitial fibrosis; Apoptosis; MAPK pathway; NADPH oxidase; Nox4
资金
- Major State Basic Research Development Program of China (973 Program) [2012CB517700]
- Key Basic Research Project of the Science and Technology Commission of Shanghai Municipality [10JC1413000]
- Construction of Key Diseases on Integrative Medicine of Shanghai [zxbz2012-19]
- Natural Science Foundation of Shanghai [13ZR1432600]
- National Natural Science Foundation of China [81270822]
Glycated albumin (GA), an Amadori product used as a marker of hyperglycemia and the early-stage glycation products compared to AGEs, might further promote kidney lesions in diabetic nephropathy (DN). However, the mechanisms how GA cause proximal tubular cells damage remain poorly understood. In this study, we investigated the effects of GA on fibrosis and apoptosis of renal proximal tubular cells (NRK-52E) in vitro experiments. Our results showed that GA promoted alpha-SMA, fibronectin (FN) and TGF-beta expressions in NRK-52E cells. GA also increased cell apoptosis and stimulated the expressions of pro-caspase 3/cleaved-caspase 3. GA overloading enhanced the phosphorylation of MAPK pathway. GA-induced alpha-SMA, FN, TGF-beta and caspase 3 expressions were completely suppressed by the NADPH oxidase inhibitor apocynin (Apo), the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the latent antioxidant Astragaloside IV (AS-IV). Real-time PCR showed that GA increased Nox1, Nox2 and Nox4 mRNA expressions, especially the Nox4 expression. Furthermore, Nox4 siRNA blocked GA-induced tubular damages and the MAPK pathway activation. These results demonstrate that GA increases the permissiveness of proximal tubular cells to fibrosis and apoptosis in vitro by triggering a pathway that involves NADPH oxidase/Nox4-MAPK signaling pathway. This event may represent a key cellular effect in increasing the susceptibility of tubular cells to fibrosis and apoptosis when the tubules cope with a high GA load. This effect is instrumental to renal damage and disease progression in patients with DN. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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