Advanced oxidation protein products induce mesangial cell perturbation through PKC-dependent activation of NADPH oxidase

2009 ◽  
Vol 296 (2) ◽  
pp. F427-F437 ◽  
Author(s):  
Xiao Fan Wei ◽  
Qiu Gen Zhou ◽  
Fan Fan Hou ◽  
Bei Yi Liu ◽  
Min Liang
Keyword(s):  
Nadph Oxidase ◽  
Mesangial Cells ◽  
Advanced Oxidation ◽  
Advanced Oxidation Protein Products ◽  
Glomerular Diseases ◽  
Regulatory Subunits ◽  
New Information ◽  
Pathogenic Factors ◽  
Underlying Mechanisms ◽  
Membrane Components

Mesangial deposition of extracellular matrix (ECM) is a hallmark of several glomerular diseases including diabetic nephropathy. Accumulation of advanced oxidation protein products (AOPPs) has been found in diabetes and chronic kidney disease and linked to mesangial ECM deposition and progressive glomerulosclerosis in these disorders. Although emerging evidence implicates AOPPs as the renal pathogenic factors, the underlying mechanisms have not been investigated. Here, using cultured rat mesangial cells (MCs) as a model, we identify AOPPs as the important mediators for activation of MC NADPH oxidase. Exposure of MCs to AOPPs, through membrane-associated phosphorylation of PKCα, induced rapid phosphorylation of cytosolic p47phox and its membrane translocation, enhanced interaction of p47phox with the membrane components p22phox and Nox4, and increased expression of these key regulatory subunits of NADPH oxidase. Challenge with AOPPs triggered cytosolic superoxide generation, resulting in upregulation of fibronectin and collagen IV genes and proteins and overexpression of TGF-β1 via a PKC-NADPH oxidase-dependent pathway, as these downstream events were blocked by the inhibitors of PKC, inhibitors of NADPH oxidase, or the cytosolic superoxide scavenger. These data provide new information for understanding the molecular basis underlying AOPP-induced MC perturbation and might be a central step toward development of new interventions.

scholarly journals Cloning and Characterization of a Novel Subunit of Protein Serine/Threonine Phosphatase 4 from Mesangial Cells

2001 ◽  
Vol 12 (12) ◽  
pp. 2601-2608 ◽  
Author(s):  
Takehiko Wada ◽  
Toshio Miyata ◽  
Reiko Inagi ◽  
Masaomi Nangaku ◽  
Masako Wagatsuma ◽  
...  
Keyword(s):  
Amino Acid ◽  
Large Scale ◽  
Cultured Cells ◽  
Mesangial Cells ◽  
Spindle Pole ◽  
Regulatory Subunit ◽  
Glomerular Diseases ◽  
Regulatory Subunits ◽  
Novel Approach

ABSTRACT. Mesangial cells play an important role in maintaining glomeruli structure and function and in the pathogenesis of glomerular diseases. With a novel approach using a rapid large-scale DNA sequencing strategy and computerized data processing, a new human gene, PP4Rmegwas cloned. The full-length cDNA clone of human PP4Rmegcoded for a novel 950-amino acid protein, which was similar to a subunit of protein serine/threonine phosphatase 4 (PP4). Recombinant PP4Rmegproduced in COS-7 cells bound to the catalytic subunit of PP4. PP4Rmegis therefore structurally and functionally related to the recently reported regulatory subunit of PP4, PP4R1. Amino acid sequence analysis of rat PP4Rmeghomologue revealed that the sequences were well conserved between human and rat (86.3% identity). Northern blot analyses of human tissues and cultured cells demonstrated that the regulatory subunits were expressed abundantly in human cultured mesangial cells, although their expression was relatively ubiquitous.In situhybridization studies in normal human renal tissues confirmed their expression in glomeruliin vivo. The expression was upregulated in glomeruli of anti-Thy1 glomerulonephritis rats before mesangial proliferation. These data demonstrate that PP4Rmegis a novel regulatory subunit of PP4, which is expressed ubiquitously but abundantly in mesangial cells. Its pathophysiologic role in mesangial cells and glomerulus remains unknown. As PP4 is an essential protein for nucleation, growth, and stabilization of microtubules at centrosomes/spindle pole bodies during cell division, PP4Rmegmay play a role in regulation of mitosis in mesangial cells.

scholarly journals Age-related accumulation of advanced oxidation protein products promotes osteoclastogenesis through disruption of redox homeostasis

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Jingshen Zhuang ◽  
Xuebing Chen ◽  
Guixing Cai ◽  
Dizheng Wu ◽  
Chen Tu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Nadph Oxidase ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Advanced Oxidation ◽  
Oxidase Inhibitor ◽  
Nuclear Factor ◽  
Advanced Oxidation Protein Products ◽  
Age Related

AbstractEnhanced osteoclastogenesis is one of the major causes of age-related bone loss. Aging is accompanied by accumulation of advanced oxidation protein products (AOPPs). However, whether AOPPs accumulation contributing to the osteoclastogenesis with aging remains unclear. Here, we showed that AOPPs accumulation was associated with the enhanced osteoclastogenesis and deterioration of bone microstructure in aged mice. In vitro, AOPPs directly induced osteoclastogenesis by interaction with receptor activator of nuclear factor κ B (RANK) and the receptor for advanced glycation end products (RAGE) in the primary bone marrow monocytes. Bindings of AOPPs to RANK and RAGE were able to activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, trigger generation of reactive oxygen species, then induce phosphorylation of mitogen-activated protein kinases and c-fos, upregulation of the nuclear factor of activated T cell c1, eventually induce bone marrow monocytes to differentiate into mature osteoclasts. Chronic exposure to AOPPs enhanced osteoclastogenesis and bone loss in mice, which could be alleviated by NADPH oxidase inhibitor apocynin. Local injection of AOPPs into subperiosteal area induced bone resorption at the site of administration, which was similar to the effect of RANK ligand. Together, these results suggested that AOPPs could serve as a novel regulator of osteoclastogenesis and AOPPs accumulation might play an important role in the development of age-related bone loss.

scholarly journals Advanced Oxidation Protein Products Promote Inflammation in Diabetic Kidney through Activation of Renal Nicotinamide Adenine Dinucleotide Phosphate Oxidase

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1829-1839 ◽  
Author(s):  
Xiao Yun Shi ◽  
Fan Fan Hou ◽  
Hong Xin Niu ◽  
Guo Bao Wang ◽  
Di Xie ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Advanced Oxidation ◽  
Diabetic Rats ◽  
Nicotinamide Adenine ◽  
Control Group ◽  
Advanced Oxidation Protein Products ◽  
Renal Inflammation ◽  
Diabetic Kidney

The involvement of inflammatory processes has been recognized in development and/or progression of diabetic nephropathy. However, the mechanisms involved in the pathogenesis of renal inflammation have not been completely understood. In this study, we tested the hypothesis that accumulation of advanced oxidation protein products (AOPPs), which occurs in diabetes, may promote inflammatory responses in diabetic kidney. Streptozotocin-induced diabetic rats were randomized to iv injection of vehicle, native rat serum albumin (RSA), and AOPPs-modified RSA (AOPPs-RSA) in the presence or absence of oral administration of apocynin. A control group was followed concurrently. Compared with RSA- or vehicle-treated diabetic rats, AOPPs-RSA-treated animals displayed significant increase in renal macrophage infiltration and overexpression of monocyte chemoattractant protein-1 and TGF-β1. This was associated with deteriorated structural and functional abnormalities of diabetic kidney, such as glomerular hypertrophy, fibronectin accumulation, and albuminuria. AOPP challenge significantly increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent superoxide generation in renal homogenates and up-regulated membrane expression of renal NADPH oxidase subunits p47phox and gp91phox. All these AOPPs-induced perturbations in diabetic kidney could be prevented by the NADPH oxidase inhibitor apocynin. These data suggest that chronic accumulation of AOPPs may promote renal inflammation in diabetes probably through activation of renal NADPH oxidase.

scholarly journals Role of NADPH Oxidase in Metabolic Disease-Related Renal Injury: An Update

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Cheng Wan ◽  
Hua Su ◽  
Chun Zhang
Keyword(s):  
Oxidative Stress ◽  
Metabolic Disease ◽  
Nadph Oxidase ◽  
Renal Injury ◽  
Mesangial Cells ◽  
Therapeutic Strategies ◽  
Metabolic Factors ◽  
Glomerular Diseases ◽  
Increased Risk

Metabolic syndrome has been linked to an increased risk of chronic kidney disease. The underlying pathogenesis of metabolic disease-related renal injury remains obscure. Accumulating evidence has shown that NADPH oxidase is a major source of intrarenal oxidative stress and is upregulated by metabolic factors leading to overproduction of ROS in podocytes, endothelial cells, and mesangial cells in glomeruli, which is closely associated with the initiation and progression of glomerular diseases. This review focuses on the role of NADPH oxidase-induced oxidative stress in the pathogenesis of metabolic disease-related renal injury. Understanding of the mechanism may help find potential therapeutic strategies.

scholarly journals Huang Gan Formula Eliminates the Oxidative Stress Effects of Advanced Oxidation Protein Products on the Divergent Regulation of the Expression of AGEs Receptors via the JAK2/STAT3 Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-11
Author(s):  
Quanwen Deng ◽  
Can Bu ◽  
Liqian Mo ◽  
Bin Lv ◽  
Shaolian Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mesangial Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Advanced Oxidation ◽  
Janus Kinase ◽  
Protective Effects ◽  
Advanced Oxidation Protein Products ◽  
Stat3 Pathway ◽  
Traditional Chinese Herbal Medicine ◽  
Jak2 Inhibitor

Chronic kidney disease (CKD) has a high prevalence and low cure rate and represents a significant health issue. Oxidative stress is common in CKD due to metabolic disorders, inflammation, and impaired renal function changing normal proteins into advanced oxidation protein products (AOPPs). Huang Gan formula (HGF) is a new type of traditional Chinese herbal medicine. Although we previously investigated the protective effects of HGF against oxidative stress, the mechanism of HGF in CKD is still not fully understood. In this study, we used western blotting, quantitative polymerase chain reaction, and biochemical assays to show that HGF significantly decreased AOPP-induced oxidative stress damage. Moreover, the protective effects of HGF might be associated with upregulation of the advanced glycation end product receptor 1 (AGE-R1) and downregulation of the receptor for advance glycation end products (RAGE). Treatment with HGF and the Janus kinase 2 (JAK2) inhibitor, AG4-90, significantly attenuated AOPP-induced JAK2/STAT3 protein levels. These findings indicate that HGF inhibits AOPP-mediated biological responses by inactivating the JAK2/STAT3 pathway. In conclusion, HGF eliminated AOPP-induced effects in human mesangial cells (HMCs) by interrupting JAK2/STAT3 signaling, which altered RAGE/AGE-R1 expression and reduced oxidative stress in CKD.

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