Modulation of Na, K-ATPase through cyclic GMP and nitric oxide pathway in central nervous system of Klotho knockout mice

• Grant number: 14/14199-6
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): January 01, 2015
• Effective date (End): August 31, 2016
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Cristoforo Scavone
• Grantee: Marina Minto Cararo Lopes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The Klotho protein has anti-aging function, and Klotho knockout mice (Kl-/-) showed a premature aging phenotype syndrome characterized by arteriosclerosis, osteoporosis, skin atrophy, cognitive decline and pulmonary emphysema. This syndrome can be reversed by restoring Klotho levels. Thus, the kl (-/-) is considered as a model of accelerated aging and it can provide important information about the function of Klotho protein in the central nervous system (CNS). A significant change in the CNS during the aging process is the decrease of the enzyme Na, K-ATPase activity, which has the function of restoring the gradients of Na+ and K+ after neuronal depolarization, and play a role in modulation of gene expression and cellular growth. Glutamate modulates Na, K-ATPase by N-methyl-D-aspartate receptor (NMDAR) which in turn can activate the neuronal nitric oxide synthase (nNOS)-cyclic GMP (cGMP) signaling cascade. This signaling cascade is decreased in aging process and it is known that decrease of Na, K-ATPase in the presence of oxidative stress has been linked to the increase of the susceptibility of the CNS to neurodegenerative processe, such as Alzheimer's disease, and dystonia pankinsoniana. With these elements in mind, the objective of this project is to investigate the changes in the function of Na, K-ATPase and the signaling pathways associated with glutamate (NMDAR-NOS-cGMP) and oxidative stress induced by the absence of Klotho protein in order to compare the behavior of these parameters in this aging model with those observed in animals subjected to normal aging. This study also aims to assess the role of Klotho as a new pharmacological strategy to mitigate the neurodegenerative processes associated with aging. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CARARO-LOPES, MARINA MINTO; YOKOYAMA MAZUCANTI, CAIO HENRIQUE; SCAVONE, CRISTOFORO; KAWAMOTO, ELISA MITIKO; BERWICK, DANIEL CHARLES. The relevance of alpha-KLOTHO to the central nervous system: Some key questions. AGEING RESEARCH REVIEWS, v. 36, p. 137-148, JUL 2017. (16/07427-8, 13/10787-8, 14/14199-6, 11/21308-8)

KAWAMOTO, E. M.; CARARO-LOPES, M. M.; KINOSHITA, P. F.; QUINTAS, L. E. M.; LIMA, L. S.; ANDREOTTI, D. Z.; SCAVONE, C.. Influence of Nitric Oxide-Cyclic GMP and Oxidative STRESS on Amyloid-beta Peptide Induced Decrease of Na,K-ATPase Activity in Rat Hippocampal Slices. Journal of Membrane Biology, v. 254, n. 5-6, SI, JUL 2021. (16/07427-8, 16/22996-9, 18/14289-6, 19/12974-6, 14/14199-6)