Novel PKC-ζ to p47 phox interaction is necessary for transformation from blebbishields.
Ontology highlight
ABSTRACT:
SUBMITTER: Jinesh GG
PROVIDER: S-EPMC4819220 | biostudies-other | 2016 Apr
REPOSITORIES: biostudies-other
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Project description:Reactive oxygen species (ROS) have an important pathogenic role in the development of many diseases, including kidney disease. Major ROS generators in the glomerulus of the kidney are the p47(phox)-containing NAPDH oxidases NOX1 and NOX2. The cytosolic p47(phox) subunit is a key regulator of the assembly and function of NOX1 and NOX2 and its expression and phosphorylation are upregulated in the course of renal injury, and have been shown to exacerbate diabetic nephropathy. However, its role in nondiabetic-mediated glomerular injury is unclear. To address this, we subjected p47(phox)-null mice to either adriamycin-mediated or partial renal ablation-mediated glomerular injury. Deletion of p47(phox) protected the mice from albuminuria and glomerulosclerosis in both injury models. Integrin ?1-null mice develop more severe glomerulosclerosis compared with wild-type mice in response to glomerular injury mainly due to increased production of ROS. Interestingly, the protective effects of p47(phox) knockout were more profound in p47(phox)/integrin ?1 double knockout mice. In vitro analysis of primary mesangial cells showed that deletion of p47(phox) led to reduced basal levels of superoxide and collagen IV production. Thus, p47(phox)-dependent NADPH oxidases are a major glomerular source of ROS, contribute to kidney injury, and are potential targets for antioxidant therapy in fibrotic disease.
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Project description:Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations of the phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Autosomal recessive p47 phox -deficient CGD (p47 phox CGD) is the second most frequent form of the disease in western countries, and more than 94% of patients have a disease-causing dinucleotide deletion (ΔGT) in the neutrophil cytosolic factor 1 (NCF1) gene. The ΔGT mutation is most likely transferred onto the NCF1 from one of its two pseudogenes co-localized on the same chromosome. The presence of NCF1 pseudogenes in healthy individuals makes the genetic diagnostics of ΔGT p47 phox CGD challenging, as it requires the distinction between ΔGT in NCF1 and in the two pseudogenes. We have developed a diagnostic tool for the identification of p47 phox CGD based on PCR co-amplification of NCF1 and its pseudogenes, followed by band intensity quantification of restriction fragment length polymorphism products. The single-day, reliable p47 phox CGD diagnostics allow for robust discrimination of homozygous ΔGT p47phox CGD patients from heterozygous carriers and healthy individuals, as well as for monitoring gene therapy efficacy.
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