Edited and Reviewed by: Berthold Hocher, Heidelberg University, Germany
*Correspondence: Jun Wada,
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In the two main forms of cell death, necrosis is characterized by disruption of the plasma membrane, release of intracellular contents, and subsequent immunogenic and inflammatory processes, while apoptosis is a regulated cell death in which dying cells with preserved plasma membrane integrity are rapidly engulfed by phagocytes and orderly cleared without promotion of inflammation. Although necrosis is an accidental cell death, several forms of regulated necrosis, such as necroptosis, pyroptosis, ferroptosis, mitochondrial permeability transition-regulated necrosis (MPT-RN), autosis, and NETosis (neutrophil extracellular traps; NETs), are controlled by specific molecular machinery and programs, which are modulated by their corresponding inhibitor.
Necroptosis is triggered by various stimuli including the activation of death receptors (FAS and TNFRSF1A) and toll-like receptors. Subsequently, the receptor-interacting serine/threonine kinase 3 (RIPK3) is activated, which further activates mixed lineage kinase domain-like pseudokinase (MLKL) and induces membrane rupture.
Pyroptosis is initiated by pathogen-associated molecular pattern molecules (PAMPs) and damage-associated molecular patterns (DAMPs), activation of caspase 1 (CASP1) or CASP11, which cleaves gasdermin D (GSDMD) to produce a 22-kDa C-terminal (GSDMD-C) and a 31-kDa N-terminal fragment (GSDMD-N). Finally, GSDMD-N induces plasma membrane rupture and pyroptosis.
Ferroptosis is induced by iron-accumulation-induced reactive oxygen species (ROS) production and impaired antioxidants system against lipid peroxidation. In the former, lipid oxidation pathway involving acyl-CoA synthetase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and arachidonate lipoxygenases 15 (ALOX15) is required for lipid oxidation in ferroptosis. In addition, the reduction in protective system including solute carrier family 7 member 11 (SLC7A11), phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4), and transcription factor nuclear factor, erythroid 2 like 2 (NFE2L2, also known as NRF2) is also involved.
In this Research Topic, two review articles focus on diabetic nephropathy. Recently, the concept of “diabetic tubulopathy” has emerged, and “tubulocentric theory” arouses the broad attention, since SGLT2 inhibitors demonstrate the significant therapeutic potential against the progression of diabetic nephropathy.
JW drafted the editorial. All authors contributed to editing the manuscript. All authors contributed to the article and approved the submitted version.
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