EFFECT OF MITOCHONDRIAL TRANSPLANTATION ON CELLULAR AND KIDNEY INJURY IN MODELS OF HYPOXIA IN VITRO AND IN VIVO.

• Grant number: 24/16112-7
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2025
• End date: August 31, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Mirian Aparecida Boim
• Grantee: Mirian Aparecida Boim
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Edgar Maquigussa

Abstract

Mitochondrial dysfunction plays a relevant role in the pathophysiology of ischemic acute kidney injury (AKI) by mediating cellular changes induced by hypoxia. Mitochondria and their components can be secreted by cells and stimulate receptor cells, influencing several cellular processes, including metabolic and inflammatory ones. However, little is known about the effect of mitochondria isolated from cells in normoxia or hypoxia on recipient cells and organs in a context related to tissue hypoxia. Our hypothesis is that mitochondria from cells in culture, under normoxic or hypoxic conditions, can influence the function of isolated recipient cells or even the ischemic kidney. The objective of this study is to evaluate the impact of exogenous mitochondria transplantation on tubular cell function and renal function in in vitro and in vivo models of hypoxia. In the in vitro model, proximal tubular epithelial cells (mm55K) will be cultured under normoxic and hypoxic conditions (94% N2, 5% CO2 and 1% O2) for 48 hours. Mitochondria isolated from these 2 groups of cells will be quantified by flow cytometry. Subsequently, mm55K cells under normoxic or hypoxic conditions will be exposed to isolated mitochondria for 24 hours. The effect of incorporating exogenous mitochondria will be evaluated on the gene and protein expression of markers of cell viability, extracellular matrix, inflammation, oxidative stress, apoptosis and oxidative metabolism. In the in vivo model, AKI will be induced by bilateral ischemia for 45 minutes followed by reperfusion (I/R) for 7 days (medium term) in mice. Mitochondria isolated from mm55K cells will be administered intravenously soon after release from the renal arteries. The effect of mitochondrial treatment will also be evaluated in the long term, 3 months after the ischemia episode. The effect of mitochondria transplantation will be evaluated on the speed of recovery of kidney function and on the long-term stability of function. The results of this study may open up possibilities for a preventive or even therapeutic strategy in situations of kidney damage resulting from ischemia. (AU)