Role of peroxisomal biogenesis in the protective effects of caloric restriction in cisplatin-induced Acute Kidney Injury

• Grant number: 22/16820-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2023
• End date: April 30, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Thaís Alves da Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology, AP.TEM

Abstract

Cisplatin is a potent antitumoral drug for diverse tumor types. However, its nephrotoxic adverse effects limit its clinical use in cancer therapy. Faced with this, several non-pharmacological approaches have been studied to minimize cisplatin-induced renal inflammation. One of these non-pharmacological approaches is caloric restriction, which several studies have demonstrated to be efficient in renal protection. However, the mechanisms underlying these effects are not fully understood. Despite this, some cellular and molecular effects have been demonstrated to be mediated by caloric restriction. The caloric restriction seems to increase autophagy and lipid metabolism as well as reduce inflammation and mitochondrial oxidative stress. Even knowing that peroxisomal biogenesis disorder induces mitochondrial dysfunction, which increases oxidative stress, and that peroxisomes are directly involved in the metabolism of lipids and reactive oxygen species, no studies have been carried out to investigate peroxisome function on caloric restriction outcomes. Therefore, our hypothesis is that peroxisomal biogenesis dysfunction in renal proximal tubular epithelial cells will cause oxidative stress and reduce lipid metabolism, abrogating the renoprotective effects of caloric restriction. For this, we will seek to investigate the role of peroxisomal biogenesis in preventing inflammation by caloric restriction in cisplatin-induced kidney injury, using experimental strategies such as: 1) C57BL/6 wild-type (WT), Kap2-iCre, Pex16flox, and peroxisomal biogenesis dysfunction (Kap2-iCre-Pex16flox) mice; 2) In vitro assays - caloric restriction effects on renal tubular epithelial cells cisplatin-treated metabolism; 3) In vivo assays - peroxisomal biogenesis disorder in cisplatin-induced renal inflammation; 4) In vivo assays - mechanisms involved in the caloric restriction effects to prevent renal inflammation. The results obtained in this project may contribute to understanding the participation of peroxisomal biogenesis on the renoprotective effects of caloric restriction, in addition to opening perspectives for future therapeutic interventions to control inflammatory processes induced by cisplatin. (AU)