Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease

Abstract

Severe and recurrent cisplatin-induced acute kidney injury (AKI) as part of standard cancer therapy is a known risk factor for development of chronic kidney disease (CKD). The specific role of superoxide (O2•-)-mediated disruption of mitochondrial oxidative metabolism in CKD after cisplatin treatment is unexplored. Cisplatin is typically administered in weekly or tri-weekly cycles as part of standard cancer therapy. To investigate the role of O2•- in predisposing patients to future renal injury and in CKD, mice were treated with cisplatin and a mitochondrial-specific, superoxide dismutase (SOD) mimetic, GC4419. Renal function, biomarkers of oxidative stress, mitochondrial oxidative metabolism, and kidney injury markers, as well as renal histology, were assessed to evaluate the cellular changes that occur one week and one month (CKD phase) after the cisplatin insult. Cisplatin treatment resulted in persistent upregulation of kidney injury markers, increased steady-state levels of O2•-, increased O2•--mediated renal tubules damage, and upregulation of mitochondrial electron transport chain (ETC) complex I activity both one week and one month following cisplatin treatment. Treatment with a novel, clinically relevant, small-molecule superoxide dismutase (SOD) mimetic, GC4419, restored mitochondrial ETC complex I activity to control levels without affecting complexes II–IV activity, as well as ameliorated cisplatin-induced kidney injury. These data support the hypothesis that increased mitochondrial O2•- following cisplatin administration, as a result of disruptions of mitochondrial metabolism, may be an important contributor to both AKI and CKD progression.

Salusin-β mediates tubular cell apoptosis in acute kidney injury: Involvement of the PKC/ROS signaling pathway

“…It is generally accepted that the development and progression of both acute and chronic kidney diseases may be primarily attributed to the imbalanced molecular mechanisms that govern oxidative stress [50]. The superoxide anions-mediated renal tubules damage may be an important contributor to the progression of AKI [51]. In light of oxidative stress, salusin-β is recently proposed as an oxidation inducer in brain tissues, VSMCs and endothelial cells in multiple disease scenarios [23,28,52].…”

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

“…Following renal uptake, cisplatin in the cytoplasm is hydrolyzed into a positively charged electrophile that can accumulate within the negatively charged mitochondrial membrane and disrupt its membrane potential [46]. This, in turn, induces superoxide generation by negatively affecting mitochondrial metabolism, the efficiency of the ETC, and ATP production [47]. Cisplatin-induced nephrotoxicity is also associated with increased DRP1-mediated mitochondrial fragmentation, cytochrome c release, apoptosis of proximal tubular cells, and renal injury [38].…”

The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

“…In cisplatin-associated AKI, mitochondrial dysfunction associated oxidative stress leads to intracellular reactive oxygen species (ROS) accumulation. Previous research showed that cisplatin administration is followed by increased oxidative stress levels and alteration in the expression of various antioxidant enzymes [96,97,98]. Mitochondria is the home of the cellular ATP synthesis and the main source of ROS production.…”