Mitochondrial Superoxide Dismutase in Cisplatin-Induced Kidney Injury

Abstract

Cisplatin is a chemotherapy agent commonly used to treat a wide variety of cancers. Despite the potential for both severe acute and chronic side effects, it remains a preferred therapeutic option for many malignancies due to its potent anti-tumor activity. Common cisplatin-associated side-effects include acute kidney injury (AKI) and chronic kidney disease (CKD). These renal injuries may cause delays and potentially cessation of cisplatin therapy and have long-term effects on renal function reserve. Thus, developing mechanism-based interventional strategies that minimize cisplatin-associated kidney injury without reducing efficacy would be of great benefit. In addition to its action of cross-linking DNA, cisplatin has been shown to affect mitochondrial metabolism, resulting in mitochondrially derived reactive oxygen species (ROS). Increased ROS formation in renal proximal convoluted tubule cells is associated with cisplatin-induced AKI and CKD. We review the mechanisms by which cisplatin may induce AKI and CKD and discuss the potential of mitochondrial superoxide dismutase mimetics to prevent platinum-associated nephrotoxicity.

Receptor of Advanced Glycation End Products Deficiency Attenuates Cisplatin-Induced Acute Nephrotoxicity by Inhibiting Apoptosis, Inflammation and Restoring Fatty Acid Oxidation

“…The exploration of the molecular mechanisms of cisplatin nephrotoxicity has never halted; however, the mechanisms have yet been fully defined, so therapies that can abolish cisplatin-induced AKI always remain lacking ( McSweeney et al, 2021 ). Studies have demonstrated that cisplatin nephrotoxicity links to mitochondrial damage, oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, necroptosis ( Xu et al, 2015 ; Zahedi et al, 2017 ; Lu et al, 2020 ; Mapuskar et al, 2021 ), etc. According to recent reports, impaired fatty acid oxidation (FAO) plays a key role in the process of cisplatin nephrotoxicity ( Chiba et al, 2019 ; Jang et al, 2020 ).…”

Magnesium Lithospermate B Protects Against Cisplatin-Induced Acute Kidney Injury via Alleviating Mitochondrial Dysfunction

“… 4 Therefore, cisplatin can disrupt mitochondrial homeostasis, which results in over-fission of mitochondria in the kidney and lung. 25 , 26 During fission, Drp1 oligomerizes around the mitochondria to form a ring structure that uses the energy generated by GTP hydrolysis to divide the mitochondria. 27 In STZ-induced diabetic mice, the increase in Drp1 expression was accompanied by mitochondrial and cardiac dysfunction.…”

“…Previous studies have found that accumulation of cisplatin in renal tubular cells induces excessive production of ROS, 26 which contributes to cisplatin-induced AKI. However, antioxidant supplementation is effective for renal protection, 4 , 37 , 38 and Salvia miltiorrhiza Bunge exerts effective antioxidant effects by donating numerous hydrogen atoms.…”

“…4 Therefore, cisplatin can disrupt mitochondrial homeostasis, which results in over-fission of mitochondria in the kidney and lung. 25,26 During fission, Drp1 oligomerizes…”

Tubular Mitochondrial Dysfunction, Oxidative Stress, and Progression of Chronic Kidney Disease

“…The use of the antineoplastic agent cisplatin is limited by nephrotoxicity, especially by AKI that may become irreversible (AKI-to-CKD transition). Preclinical studies support a role for mitochondrial dysfunction in cisplatin-AKI [ 39 , 40 , 41 ]. Cisplatin nephrotoxicity is characterized by mtROS production, reduced mitochondrial membrane potential, mitochondrial swelling, and loss of mitochondrial function [ 42 ].…”