title: Glycated albumin triggers fibrosis and apoptosis via an NADPH oxidase/Nox4-MAPK pathway-dependent mechanism in renal proximal tubular cells.
abstract: 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 α-SMA, fibronectin (FN) and TGF-β 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 α-SMA, FN, TGF-β 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.
authors: Nephrology Department, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
authors: Weiwei
authors: W
authors: Qi
authors: Nephrology Department, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
authors: Jianying
authors: J
authors: Niu
authors: Nephrology Department, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
authors: Qiaojing
authors: Q
authors: Qin
authors: School of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai 200240, China.
authors: Zhongdong
authors: Z
authors: Qiao
authors: Nephrology Department, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China; Nephrology Department, Huashan Hospital, Fudan University, Shanghai 200240, China. Electronic address: yonggu@vip.163.com.
authors: Yong
authors: Y
authors: Gu
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D017127:Glycation End Products, Advanced; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000473:pathology*; D020935:MAP Kinase Signaling System; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012709:Serum Albumin / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000093423:Glycated Serum Albumin
chemical_list: D000098:Acetophenones; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D012709:Serum Albumin; D016212:Transforming Growth Factor beta; C056165:acetovanillone; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D000093423:Glycated Serum Albumin
keywords: Apoptosis; GA; MAPK pathway; NADPH oxidase; Nox4; Tubulointerstitial fibrosis