The clinical relevance of necroinflammation—highlighting the importance of acute kidney injury and the adrenal glands

Tonnus, Wulf; Gembardt, Florian; Latk, Markus; Parmentier, Simon; Hugo, Christian; Bornstein, Stefan R.; Linkermann, Andreas

doi:10.1038/s41418-018-0193-5

Cited by 32 publications

(30 citation statements)

References 195 publications

(191 reference statements)

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“…Ferroptosis is an iron-dependent form of cell death associated with increased lipid peroxidation 18 , shown to be fully independent of caspase activity 19 and pathophysiological roles for this cell death have been described in ischemic injuries such as renal failure 20,21 . Ferroptosis is tightly regulated by glutathione peroxidase 4 (GPX4) 22 which belongs to the family of GPX enzymes that are able to reduce hydroperoxides at the expenses of two molecules of glutathione (GSH) 23 .…”

Section: Introductionmentioning

confidence: 99%

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

et al. 2020

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Conditions of impaired adrenal function and tissue destruction, such as in Addison's disease, and treatment resistance of adrenocortical carcinoma (ACC) necessitate improved understanding of the pathophysiology of adrenal cell death. Due to relevant oxidative processes in the adrenal cortex, our study investigated the role of ferroptosis, an irondependent cell death mechanism and found high adrenocortical expression of glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4) genes, key factors in the initiation of ferroptosis. By applying MALDI mass spectrometry imaging to normal and neoplastic adrenocortical tissue, we detected high abundance of arachidonic and adrenic acid, two long chain polyunsaturated fatty acids which undergo peroxidation during ferroptosis. In three available adrenal cortex cell models (H295R, CU-ACC1 and CU-ACC-2) a high susceptibility to GPX4 inhibition with RSL3 was documented with EC 50 values of 5.7 × 10 −8 , 8.1 × 10 −7 and 2.1 × 10 −8 M, respectively, while all nonsteroidogenic cells were significantly less sensitive. Complete block of GPX4 activity by RSL3 led to ferroptosis which was completely reversed in adrenal cortex cells by inhibition of steroidogenesis with ketoconazole but not by blocking the final step of cortisol synthesis with metyrapone. Mitotane, the only approved drug for ACC did not induce ferroptosis, despite strong induction of lipid peroxidation in ACC cells. Together, this report is the first to demonstrate extraordinary sensitivity of adrenal cortex cells to ferroptosis dependent on their active steroid synthetic pathways. Mitotane does not induce this form of cell death in ACC cells.

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Section: Introductionmentioning

confidence: 99%

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

et al. 2020

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“…Among them, renal tubular cell death is a common histopathological feature of AKI, and it is generally considered to be one of the factors leading to impaired renal function [30]. Pyroptosis is a proin ammatory programmed cell death regulated by caspases, and its role in kidney damage has been gradually discovered in recent years [9,31]. The role of pyroptosis of RTECs in cisplatin-induced AKI has been reported [12].…”

Section: Discussionmentioning

confidence: 99%

Cisplatin induces acute kidney injury and pyroptosis in mice through the exosome miR-122/ELAVL1 regulatory axis

Zhu¹,

Ye²,

Gao³

et al. 2020

Preprint

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Background Although cisplatin is an effective chemotherapeutic drug for the treatment of various cancers, its clinical application is limited due to its side effects, especially nephrotoxicity. Unfortunately, Acute kidney injury (AKI) caused by cisplatin remains one of the main obstacles to cancer treatment. Increasing evidence suggests that renal inflammation and pyroptotic inflammatory cell death of tubular epithelial cells (RTECs) mainly determine the progression and outcome of cisplatin-induced AKI. However, it is not clear how cisplatin regulates the pyroptosis of RTECs cells in AKI. The current study aimed to determine the regulation mechanism of AKI induced by cisplatin. In vivo, cisplatin was used to induce AKI. H&E staining of mouse kidney tissue sections and serological indicators of kidney injury (including BUN, serum creatinine and TNF-α) were detected. The important substrate protein GSDMD and key target caspase-1 of pyroptosis were detected by immunohistochemistry and western blot, respectively. In vitro, cisplatin significantly induces HK-2 cells pyroptosis. Furthermore, Cisplatin transmits HK2 cells pyroptosis signals to surrounding cells in the form of exosomes. Previous studies have shown that exosomes are involved in kidney physiology and the pathogenesis of various kidney diseases/disorders. MicroRNAs (miRNAs) are the main functional components of exosomes. Results Further research shows that exosome miR-122 negatively regulates the pyrolysis of HK2 cells. Finally, we elucidated that exosome miR-122 participates in cisplatin induced AKI regulation by regulating ELAVL1 expression. Conclusions In conclusion, these results suggest that exosome miR-122 inhibits pyroptosis and AKI by targeting ELAVL1 under cisplatin treatment, which will provide a potential target for the treatment of AKI.

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“…Although sublethal injury may be reversible, the death of tubular cells triggers a release of DAMPs which could in turn, amplify inflammation ( 14 ). This cascade is called necroinflammation and produces a downward cascade after the primary damage and participates in kidney failure with immune cell infiltration ( 67 ). Several studies have pointed out that the level of DAMPs was correlated with survival during sepsis ( 68 , 69 ).…”

Section: Pathophysiology Of Septic Akimentioning

confidence: 99%

Role of Damage-Associated Molecular Patterns in Septic Acute Kidney Injury, From Injury to Recovery

et al. 2021

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Damage-associated molecular patterns (DAMPs) are a group of immunostimulatory molecules, which take part in inflammatory response after tissue injury. Kidney-specific DAMPs include Tamm-Horsfall glycoprotein, crystals, and uromodulin, released by tubular damage for example. Non-kidney-specific DAMPs include intracellular particles such as nucleus [histones, high-mobility group box 1 protein (HMGB1)] and cytosol parts. DAMPs trigger innate immunity by activating the NRLP3 inflammasome, G-protein coupled class receptors or the Toll-like receptor. Tubular necrosis leads to acute kidney injury (AKI) in either septic, ischemic or toxic conditions. Tubular necrosis releases DAMPs such as histones and HMGB1 and increases vascular permeability, which perpetuates shock and hypoperfusion via Toll Like Receptors. In acute tubular necrosis, intracellular abundance of NADPH may explain a chain reaction where necrosis spreads from cell to cell. The nature AKI in intensive care units does not have preclinical models that meet a variation of blood perfusion or a variation of glomerular filtration within hours before catecholamine infusion. However, the dampening of several DAMPs in AKI could provide organ protection. Research should be focused on the numerous pathophysiological pathways to identify the relative contribution to renal dysfunction. The therapeutic perspectives could be strategies to suppress side effect of DAMPs and to promote renal function regeneration.

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The clinical relevance of necroinflammation—highlighting the importance of acute kidney injury and the adrenal glands

Cited by 32 publications

References 195 publications

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

Cisplatin induces acute kidney injury and pyroptosis in mice through the exosome miR-122/ELAVL1 regulatory axis

Role of Damage-Associated Molecular Patterns in Septic Acute Kidney Injury, From Injury to Recovery

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