Evaluation of physical exercise effects on cognitive impairment induced by nefrectomy in mice

• Grant number: 23/15535-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2024
• End date: April 30, 2028
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Elisa Mitiko Kawamoto Iwashe
• Grantee: Thays Calista Santiago Pretes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 21/06009-6 - Neuroplasticity -induced by challenge Na, K-ATPase, Klotho, glutamate, and neuroinflammation signaling cascades to reveal new therapeutic targets for aging and neurodegenerative diseases, AP.TEM

Abstract

The Klotho gene has been associated with longevity in mice, demonstrating accelerated early aging after silencing or increased life expectancy when the gene is overexpressed.The Klotho protein has transmembrane and secreted forms, with distinct functions, among them the regulation of ion channels and growth factor receptors. In addition to acting as a co-receptor for fibroblast growth factor (FGF23), maintaining phosphate and vitamin D homeostasis, including renal secretion and bone fixation. Regardingcognition, reduced levels of Klotho expression were associated with cognitive damageand weakness, while its increase can stimulate neurogenesis and exert neuroprotective effects, especially in neurodegenerative diseases such as Alzheimer's, demonstrated in rodents and patients, by different groups. Physical exercise has been associated with increased expression of Klotho, providing benefits that include increased longevity and cognitive improvement. Meanwhile, chronic kidney disease (CKD) affects about 10-12%of the population, resulting in systemic complications and cognitive disorders due tochronic inflammation. CKD may also be related to blood-brain barrier dysfunction (BBB),possibly causing neurological damage. Changes in BBB have been associated with neurodegenerative diseases such as Parkinson's disease and with mental disorders such as depression and schizophrenia. In summary, the involvement of Klotho has been described as crucial in the development of cognitive processes and protection against neurodegeneration, in addition to being related to the dysfunctions of BBB associatedwith CKD. From these findings, we propose to evaluate the expression of Klotho proteinand cognitive performance modulated by voluntary physical exercise in a model of cognitive impairment induced by nephrectomy. In this context, physical exercise emerges as a promising intervention to increase the expression of Klotho, improving cognitive health and reducing the negative impacts of neurodegenerative and renaldiseases. Still, the complexity of the mechanisms involved in the modulation of Klothorequires further investigation for a complete understanding of its role in CKD. (AU)