Autophagy and necroptosis in cisplatin-induced acute kidney injury: Recent advances regarding their role and therapeutic potential

Abstract

Cisplatin (CP) is a broad-spectrum antineoplastic agent, used to treat many different types of malignancies due to its high efficacy and low cost. However, its use is largely limited by acute kidney injury (AKI), which, if left untreated, may progress to cause irreversible chronic renal dysfunction. Despite substantial research, the exact mechanisms of CP-induced AKI are still so far unclear and effective therapies are lacking and desperately needed. In recent years, necroptosis, a novel subtype of regulated necrosis, and autophagy, a form of homeostatic housekeeping mechanism have witnessed a burgeoning interest owing to their potential to regulate and alleviate CP-induced AKI. In this review, we elucidate in detail the molecular mechanisms and potential roles of both autophagy and necroptosis in CP-induced AKI. We also explore the potential of targeting these pathways to overcome CP-induced AKI according to recent advances.

Cisplatin Nephrotoxicity Is Critically Mediated by the Availability of BECLIN1

“…Technically, more extensive control data such as CASPASE3 assessment in Becn1 +/− mice would be desirable. Furthermore, previous studies showed that other pathways of cell death such as necroptosis and ferroptosis play an important role in cisplatin nephropathy and these pathways were not in the scope of our study [ 60 , 61 , 62 , 63 ]. Also, inflammatory pathways with various mediators including tumor necrosis factor alpha (TNFα), toll-like receptor (TLR) signaling and chemokine (C-X-C motif) ligand (CXCL) 16 and the CXCL1-CXCR 2 axis have been shown to contribute to renal deterioration in cisplatin nephropathy [ 54 , 64 , 65 , 66 , 67 , 68 ].…”

Protective Role of Betulinic Acid against Cisplatin-Induced Nephrotoxicity and Its Antibacterial Potential toward Uropathogenic Bacteria

“…Meanwhile, ATG5 is recruited and helps activate the closure of the autophagosomes [ 27 ]. It was also stated that the cisplatin injection was associated with suppressing autophagic LC3II expression [ 28 ], and the more autophagy got inhibited, the worse kidney function got [ 26 , 29 , 30 ]. In the current study, mice treated with cisplatin showed substantial repression in the gene expression of Beclin 1, ATG5, as well as inhibition of LC3-II gene expression.…”

Mitochondrial Signaling, the Mechanisms of AKI-to-CKD Transition and Potential Treatment Targets

“…Experimental investigations have remarkably illuminated promising strategies for enhancing AKI prognosis through the modulation of mitochondrial function. Notably, instances of AKI induced by both ischemia and cisplatin showcased significant amelioration when apoptosis was strategically inhibited through the ablation of Bax and Bak [105,106]. This groundbreaking revelation highlights the intricate connection between mitochondrial dynamics and the apoptotic cascade, shedding light on potential therapeutic targets for preventing AKI progression.…”

“…Mitochondria are also central to the initiation of AKI, potentially paving the way for the transition to CKD following exposure to nephrotoxic agents [108]. Maleic acid (MA)induced AKI, notably affecting renal proximal tubules, is associated with mitochondrial dysfunction [105,106]. MA-induced kidney injuries impact renal ammoniagenesis and mitochondrial energy homeostasis and induce mitochondrial permeability transition pore opening, leading to cell apoptosis [109][110][111].…”