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.
Subject(s)
Apoptosis , Doxorubicin , Kidney , Mitochondria , NF-E2-Related Factor 2 , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Phosphocreatine , Doxorubicin/toxicity , Animals , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Apoptosis/drug effects , NF-E2-Related Factor 2/metabolism , Rats , Mitochondria/drug effects , Mitochondria/metabolism , Male , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Phosphocreatine/metabolism , Rats, Wistar , Signal Transduction/drug effects , Oxidative Stress/drug effects , Kidney Diseases/chemically induced , Kidney Diseases/metabolism , Kidney Diseases/drug therapy , Kidney Diseases/pathologyABSTRACT
Diabetic retinopathy (DR) stands as a prevalent complication of diabetes mellitus, causing damage to the delicate retinal capillaries and potentially leading to visual impairment. While the exact underlying cause of DR remains elusive, compelling research suggests that mitochondrial energy deficiency and the excessive generation of reactive oxygen species (ROS) play pivotal roles in its pathogenesis. Recognizing that controlling hyperglycemia alone fails to reverse the defects in retinal mitochondria induced by diabetes, current strategies seek to restore mitochondrial function as a means of safeguarding against DR. To address this pressing issue, a comprehensive study was undertaken to explore the potential of phosphocreatine (PCr) in bolstering mitochondrial bioenergetics and providing protection against DR via modulation of the JAK2/STAT3 signaling pathway. Employing rat mitochondria and RGC-5 cells, the investigation meticulously assessed the impact of PCr on ROS production, mitochondrial membrane potential, as well as the expression of crucial apoptotic and JAK2/STAT3 signaling pathway proteins, utilizing cutting-edge techniques such as high-resolution respirometry and western blotting. The remarkable outcomes revealed that PCr exerts a profound protective influence against DR by enhancing mitochondrial function and alleviating diabetes-associated symptoms and biochemical markers. Notably, PCr administration resulted in an upregulation of antiapoptotic proteins, concomitant with a downregulation of proapoptotic proteins and the JAK2/STAT3 signaling pathway. These significant findings firmly establish PCr as a potential therapeutic avenue for combating diabetic retinopathy. By augmenting mitochondrial function and exerting antiapoptotic effects via the JAK2/STAT3 signaling pathway, PCr demonstrates promising efficacy both in vivo and in vitro, particularly in counteracting the oxidative stress engendered by hyperglycemia. In summary, our study sheds light on the potential of PCr as an innovative therapeutic strategy for diabetic retinopathy. By bolstering mitochondrial function and exerting protective effects via the modulation of the JAK2/STAT3 signaling pathway, PCr holds immense promise in ameliorating the impact of DR in the face of oxidative stress induced by hyperglycemia.