Oxidative stress induces inactivation of protein phosphatase 2A,promoting proinflammatory NF-κB in aged rat kidney |
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| Institution: | 1. Analytical Center, Korea Institute of Toxicology, Yuseong, Daejeon 305-343, Republic of Korea;2. Department of Pharmacy, College of Pharmacy and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 609-735, Republic of Korea;3. Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea;4. Department of Physiology, The University of Texas Health Science Center, San Antonio, TX, USA;1. Department of Biological Chemistry, University of Athens Medical School, 11527 Athens, Greece;1. Breast Cancer Research Centre-Western Australia, Perth, WA, Australia;2. International Drug Development Institute, San Francisco, CA;3. I-BioStat, Hasselt University, Belgium;4. Puma Biotechnology Inc, Los Angeles, CA, USA;1. Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India;2. Histopatholgy, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India;3. Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India;1. NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;2. Multiple Sclerosis Centre, Klinik Hennigsdorf, Germany;1. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt;2. Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt;3. Department of Animal Wealth Development, Genetics and Genetic Engineering, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh, Egypt;4. Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh, Egypt |
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| Abstract: | The molecular inflammation hypothesis of aging proposes that redox dysregulation causes an age-related activation of NF-κB and its signaling to upregulate various proinflammatory genes. In the present study, we focused on the inactive form of the protein phosphastase 2 A (PP2A). More specifically, we aimed to define the correlation between PP2A inactivation and NF-κB activation by age-related oxidative stress. Experimentations were designed to determine the effect of oxidative stress-induced PP2A inactivation on NF-κB activity, utilizing prooxidants t-BHP and AAPH, the PTP inhibitor Na3VO4, and the PP2A inhibitor Calyculin A and PP2A siRNA, in HEK293T cells. We also assessed the phosphorylation of PP2A catalytic subunit (PP2Ac) and the activities of PP2A and NF-κB in aged rat kidney, utilizing aging-retarding 40% calorie restriction (CR) −60% of food intake and inflammation-triggering LPS paradigms. Results revealed that an oxidative stress-induced PTK/PTP imbalance led to phosphorylation of PP2Ac, following exposures to t-BHP, AAPH, and Na3VO4 in HEK293T cells. Subsequently, we found that Calyculin A and PP2A siRNA activates NIK/IKK and MAPKs, leading to upregulation of NF-κB and its dependent oxidative stress. Also, the contrasting relation between PP2A inactivation and NF-κB activation was confirmed by AAPH-induced oxidative status in mice, and non-induced normal status or LPS-induced inflammatory status in aged rats while the antioxidative, anti-inflammatory, anti-aging effects of CR significantly blunted these actions. Thus, we present evidence that PP2A inactivation via PTK/PTP imbalance provoked by oxidative stress causes NF-κB activation, which contributes to the accumulation of oxidative stress in aged rat kidney. |
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| Keywords: | PP2A NF-κB Aging Oxidative stress Molecular inflammation Free radicals |
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