Reference no: EM133535433

Summarize this For over a decade, oxidative stress has been regarded as an important factor that contributes to cisplatin-induced nephrotoxicity. Researches showed that cisplatin mainly causes renal damage by inducing oxidative stress in renal tubular and glomerular cells, thereby leading to cell necrosis and apoptosis, vascular dysfunction, and strong immune response. In recent years, the mechanism of apoptosis inducing renal tubular cell dysfunction has been a focus of investigation of cisplatin nephrotoxicity. Several pathways of apoptosis have been implicated; the rst one is the extrinsic pathway mediated by death receptors, such as Fas and tumor necrosis factor-the intrinsic pathway centered on mitochondria, which relates to cellular stress that leads to the activation of the proapoptotic Bcl-2 family proteins Bax and Bak on the mitochondrial membrane [and the endoplasmic reticulum (ER) stress pathway, which is activated by caspase-12 mainly. Although the progression of apoptosis induced by cisplatin results from several precise mechanisms, oxidative stress has been widely related to them; furthermore, the relationship between oxidative stress and apoptosis might be direct as they share a similar dysregulation of mitochondria. Oxidative stress is a cellular stress response when the reduction and oxidation (redox) balance between reactive species and antioxidant species is disrupted. Oxidation is defined as the chemical reaction, which is an important part of cellular metabolism and other biological function that allows electrons to be separated from an atom or molecule. Free radicals are atoms or molecules that have unpaired electrons and are always unstable and highly reactive, of which excess accumulation usually induces oxidative stress. There are two common types of free radicals: oxygen derived radicals, also called reactive oxygen species (ROS), and nitrogen-based radicals, also called reactive nitrogen species (RNS).

All cells in the body are exposed chronically to free radicals. Antioxidants are present in serum and erythrocytes, as well as other tissues and organs to prevent damage caused by ROS, RNS, and other free radicals. The system of antioxidant is composed of molecules having antioxidant properties such as glutathione (GSH), vitamin C, transferrin, albumin, and various antioxidant enzymes, such as glutathione peroxidase. Antioxidant defense in the human body is weakened; therefore, oxidative stress occurs when the delicate balance between the amounts of oxidants and antioxidants is broken. It is worth noting that once cisplatin enters kidney cells, it rapidly induces a large accumulation of ROS in the cell, breaks the balance of the redox system in the intracellular environment, and contributes to the out leakage of several intracellular compositions that could cause different degrees of damage. ROS can also target and modify multiple molecules in the cells, such as lipids, proteins, and DNA, which can result in cellular stress [28, 39]. In addition, ROS appear to be involved in the activation of several important signaling pathways during cisplatin-induced nephrotoxicity. Some studies have confirmed that the massive accumulation of ROS and other mitochondrial oxidative stress-induced functional disorders is the early signaling of cisplatin-induced pathological events, such as inflammatory response and several apoptotic signal pathways mediated by caspases and mitogen-activated protein kinases (MAPKs). Meanwhile, researches show that other stress like nitrosative stress produces a toxic role in cisplatin-induced nephrotoxicity by another free radical, RNS [and also indicate that nitrosative stress and oxidative stress form a quantity of steps in the mechanism of cell damage together. However, this review mainly focuses on oxidative stress and ROS and discusses the mechanism of cisplatin-induced oxidative stress response that contributes to nephrotoxicity.