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Regulated cell death in chronic kidney disease: current evidence and future clinical perspectives
Kurt T K Giuliani1,2,3, Benjamin C Adams1,2,3, Helen G Healy1,2,3
1Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Brisbane, QLD, Australia.
Abstract:
Chronic kidney disease (CKD) is the progressive loss of kidney function/structure over a period of at least 3 months. It is characterised histologically by the triad of cell loss, inflammation and fibrosis. This literature review focuses on the forms of cell death that trigger downstream inflammation and fibrosis, collectively called regulated cell death (RCD) pathways. Discrete forms of RCD have emerged as central mediators of CKD pathology. In particular, pathways of regulated necrosis - including mitochondrial permeability transition pore (mPTP)-mediated necrosis, necroptosis, ferroptosis and pyroptosis - have been shown to mediate kidney pathology directly or through the release of danger signals that trigger a pro-inflammatory response, further amplifying tissue injury in a cellular process called necroinflammation. Despite accumulating evidence in pre-clinical models, no clinical studies have yet targeted these RCD modes in human CKD. The review summarizes recent advances in our understanding of RCD pathways in CKD, looks at inter-relations between the pathways (with the emphasis on propagation of death signals) and the evidence for therapeutic targeting of molecules in the RCD pathways to prevent or treat CKD.
Insights
Regulated cell death (RCD) pathways drive inflammation and fibrosis in chronic kidney disease (CKD). Targeting these pathways offers potential therapeutic strategies for CKD, though clinical studies are lacking.
Area of Science:
- Nephrology
- Cell Biology
- Pathology
Background:
- Chronic kidney disease (CKD) involves progressive kidney function loss, characterized by cell loss, inflammation, and fibrosis.
- Regulated cell death (RCD) pathways are increasingly recognized as key mediators of CKD pathology.
Purpose of the Study:
- To review the role of RCD pathways in triggering inflammation and fibrosis in CKD.
- To explore the interconnections between different RCD pathways and their signaling.
- To assess the therapeutic potential of targeting RCD pathways for CKD treatment.
Main Methods:
- Literature review of pre-clinical and clinical studies on RCD in CKD.
- Analysis of histological characteristics of CKD, focusing on cell death mechanisms.
- Examination of signaling pathways involved in necroinflammation.
Main Results:
- Specific RCD pathways, including regulated necrosis (mPTP-mediated necrosis, necroptosis, ferroptosis, pyroptosis), directly contribute to kidney pathology.
- These pathways release danger signals, promoting pro-inflammatory responses and amplifying tissue injury (necroinflammation).
- Despite strong pre-clinical evidence, no clinical trials have targeted RCD pathways in human CKD.
Conclusions:
- RCD pathways are central to the inflammatory and fibrotic processes in CKD.
- Understanding the interplay between RCD pathways is crucial for developing effective therapies.
- Targeting RCD offers a promising, yet unexplored, therapeutic avenue for managing CKD.
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