title: Oxidative stress induces inactivation of protein phosphatase 2A, promoting proinflammatory NF-κB in aged rat kidney.
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 2A (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.
authors.affiliation: Analytical Center, Korea Institute of Toxicology, Yuseong, Daejeon 305-343, Republic of Korea; Department of Pharmacy, College of Pharmacy and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Kyung
authors.initials: K
authors.lastname: Jin Jung
authors.affiliation: Department of Pharmacy, College of Pharmacy and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Dae
authors.initials: D
authors.lastname: Hyun Kim
authors.affiliation: Department of Pharmacy, College of Pharmacy and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 609-735, Republic of Korea; Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Eun
authors.initials: E
authors.lastname: Kyeong Lee
authors.affiliation: Analytical Center, Korea Institute of Toxicology, Yuseong, Daejeon 305-343, Republic of Korea.
authors.forename: Chang
authors.initials: C
authors.lastname: Woo Song
authors.affiliation: Department of Pharmacy, College of Pharmacy and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 609-735, Republic of Korea; Department of Physiology, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Byung
authors.initials: B
authors.lastname: Pal Yu
authors.affiliation: Department of Pharmacy, College of Pharmacy and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 609-735, Republic of Korea. Electronic address: hyjung@pusan.ac.kr.
authors.forename: Hae
authors.initials: H
authors.lastname: Young Chung
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008387:Marine Toxins; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D018384:Oxidative Stress; D054648:Protein Phosphatase 2 / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D008387:Marine Toxins; D016328:NF-kappa B; D010080:Oxazoles; C059041:calyculin A; D011505:Protein-Tyrosine Kinases; D054648:Protein Phosphatase 2
keywords: Aging; Free radicals; Molecular inflammation; NF-κB; Oxidative stress; PP2A