NOX-mediated impairment of PDGF-induced DNA synthesis in peripheral blood lymphocytes of children with idiopathic nephrotic syndrome

Abstract

BackgroundCellular oxidative stress, inflammatory responses, and immunogenic events are involved in pathogenesis of idiopathic nephrotic syndrome (INS); however, the exact mechanism remains unknown. We examined NADPH oxidase (NOX) activity and platelet-derived growth factor (PDGF)-induced DNA synthesis in peripheral blood lymphocytes (PBL) of patients with INS.MethodsPBL from 15 patients with INS and 15 age- and gender-matched controls were isolated, and enzyme activities of NOX, catalase, and superoxide dismutase (SOD) were measured along with the assay of malondialdehyde levels and bromo-deoxyuridine incorporation. Protein expression of NOX-1 was measured using western blot analysis.ResultsPatients with INS had significantly (P<0.01) higher NOX activity and increased protein expression of NOX-1 in PBL as compared with controls. Catalase and SOD activities were markedly lower with lipid peroxide levels significantly (P<0.01) increased in patients with INS. Ex vivo DNA synthesis in PDGF-stimulated PBL was significantly (P<0.01) reduced in patients with INS; however, diphenyliodonium, an inhibitor of NOX, markedly corrected impairment in growth factor-induced BrdU incorporation.ConclusionsThese results show that NOX activation might have a role in regulation of lymphocytic activity in patients with INS through the impairment of PDGF mitogenic function and might contribute toward pathogenesis of nephrotic syndrome.

Self-Sustained Regulation or Self-Perpetuating Dysregulation: ROS-dependent HIF-YAP-Notch Signaling as a Double-Edged Sword on Stem Cell Physiology and Tumorigenesis

“…Among them, NOX are known to regulate the differentiation and self-renewal of stem cells and potentiate the self-renewal, metastasis, and drug resistance of CSCs through, for example, Notch, mitogen-activated protein kinases (MAPKs, including Erk1/2, Jun N-terminal kinase (JNK), and p38 kinase), and phosphatidyl-inositol-3-kinase- (PI3K-) AKT signaling ( Skonieczna et al, 2017 ). Crosstalk between NOX and the signaling of TGFβ1 ( Ning et al, 2002 ), BMP ( Sanchez-De-Diego et al, 2019 ), Ang II ( Nguyen Dinh Cat et al, 2013 ), PDGF ( Al-Eisa and Dhaunsi, 2017 ), EGF ( Weng et al, 2018 ), and IGF-1 ( Xi et al, 2013 ; Kang et al, 2016 ) has also been reported and/or reviewed. Moreover, NOX potentiate the interaction between ECM and cell surface receptors such as integrin β1 ( Heo and Lee, 2011 ), thereby facilitating cell adhesion and migration, particularly in the presence of niche cytokine factors such as IGF-1 ( Chiarugi et al, 2003 ; Meng et al, 2008 ; Heo and Lee, 2011 ; Xi et al, 2013 ).…”

The long and winding road to the etiology of idiopathic nephrotic syndrome in children: Focusing on abnormalities in the gut microbiota

“…In addition to ROS, biomarkers of antioxidants, including SOD, 9,[11][12][13]21,22 catalase, 21,22 glutathione peroxidase, 13,21,23 vitamin A, 23 vitamin C, 9,23 vitamin E, 9,23 carotene, 10 and riboflavin, 10 have been extensively studied in pediatric INS patients to clarify the involvement of decreased antioxidant potential in pathogenesis of the disease. In almost all studies, compared with healthy controls, antioxidant biomarkers were lower in INS patients when they had advanced proteinuria.…”

Targeting of the NOX1/ADAM17 Enzymatic Complex Regulates Soluble MCAM-Dependent Pro-Tumorigenic Activity in Colorectal Cancer

“…It has been reported that NADPH-oxidase family members, in particular NOX1 and NOX4, are expressed by cancer cells and promote tumor growth and metastasis in several cancers (i.e., melanoma, gastric, pancreatic, and colorectal cancers) [20]. They are also expressed by the cellular components of blood vessels (e.g., endothelial cells, pericytes, and vascular smooth muscle cells) and promote tumor angiogenesis [21][22][23][24]. Interestingly, the pharmacologic inhibition of NOX1, using a selective NOX1 inhibitor (GKT771) and NOX1 genetic ablation in mice, demonstrated potent anti-tumor and anti-angiogenic activities [25].…”