Contribution of metabolic pathways associated with caloric restriction on the attenuation of cisplatin-induced nephrotoxicity: direct actions and potential modulation of cell cycle pathways, regulated necrosis and DNA repair

• Grant number: 24/13998-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2024
• End date: September 30, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Juliano Zequini Polidoro
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg), AP.TEM

Abstract

The chemotherapeutic agent cisplatin has been used against solid tumors for decades, but it also causes a high incidence of acute and chronic nephrotoxicity. Cisplatin-induced renal dysfunction seems to occur due to both direct DNA damage and depletion of antioxidants in renal cells, particularly from proximal tubule. The initial injury in this segment after cisplatin treatment induce a process characterized by mitochondrial dysfunction, necrosis and inflammatory senescence, which might lead to a setting of inflammation, fibrosis and capillary rarefaction throughout the organ. Evidence suggests that the magnitude of damage and the time necessary for cell repair can determine a nephrotoxic outcome or a proper restoration of renal function after cisplatin insult. Therefore, understanding the mechanisms associated with renal recovery from cisplatin-induced damage, both at control conditions and after pharmacological and/or dietary approaches, might create new therapeutic protocols to reduce the likelihood of acute and/or chronic renal dysfunction in clinical settings. In the present project, we intend to further assess the molecular and cellular mechanisms associated with the decreased nephrotoxicity conferred by caloric restriction, including the potential contribution of classical pathways involved in metabolic reprogramming and cell cycle/DNA repair.