Phosphocreatine attenuates doxorubicin-induced nephrotoxicity through inhibition of apoptosis, and restore mitochondrial function via activation of Nrf2 and PGC-1α pathways

Abstract

Doxorubicin (DOX), a chemotherapy drug widely recognized for its efficacy in cancer treatment, unfortunately, has significant nephrotoxic effects leading to kidney damage. This study explores the nephroprotective potential of Phosphocreatine (PCr) in rats, specifically examining its influence on Nrf2 (Nuclear factor erythroid 2-related factor 2) and PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) pathways, its role in apoptosis inhibition, and effectiveness in preserving mitochondrial function. The research employed in vivo experiments in rats, focusing on PCr's capacity to protect renal function against doxorubicin-induced damage. The study entailed evaluating Nrf2 and PGC-1α pathway activation, apoptosis rates, and mitochondrial health in renal tissues. A significant aspect of this research was the use of high-resolution respirometry (HRR) to assess the function of isolated kidney mitochondria, providing in-depth insights into mitochondrial bioenergetics and respiratory efficiency under the influence of PCr and doxorubicin. Results demonstrated that PCr treatment significantly enhanced the activation of Nrf2 and PGC-1α pathways, reduced apoptosis, and preserved mitochondrial structure in doxorubicin-affected kidneys. Observations included upregulated expression of Nrf2 and PGC-1α target genes, stabilization of mitochondrial membranes, and a notable improvement in cellular antioxidant defense, evidenced by the activities of enzymes like superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) This study positions phosphocreatine as a promising agent in mitigating doxorubicin-induced kidney damage in rats. The findings, particularly the insights from HRR on isolated kidney mitochondria, highlight PCr's potential in enhancing mitochondrial function and reducing nephrotoxic side effects of chemotherapy. These encouraging results pave the way for further research into PCr's applications in cancer treatment, aiming to improve patient outcomes by managing chemotherapy-related renal injuries.